bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2026–06–14
thirty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Tumor infiltrating lymphocytes against solid tumors: current trends & perspectives.
  2. Tumor infiltrating lymphocyte (TIL) therapy for treating the solid tumors: Challenges and future perspectives.
  3. ILT2 identifies an unexploited pool of intratumoral CD8+ bystander T cells with TCR-independent cytotoxicity in renal cell carcinoma.
  4. Phenotypic Analysis of 26 Cultured TILs Derived From Japanese Melanoma Tissues.
  5. Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells.
  6. Changes in CD8-positive lymphocytes following chemotherapy with concomitant bevacizumab in HER2-negative breast cancer.
  7. Immune-cold NSCLC tumors harbor tumor-associated macrophages with elevated expression of immunoglobulin genes.
  8. A bibliometric analysis of global research trends in adoptive cell therapy for triple negative breast cancer over the past 15 years.
  9. SAFE-IOERT prospective study: clinical outcomes of exclusive intraoperative radiotherapy in early breast cancer according to molecular subtype and tumor-infiltrating lymphocytes.
  10. Tobemstomig, a novel bispecific antibody, preferentially blocks PD-1 and LAG-3 on CD8 TILs to expand stem-like T-cells for sustained tumor control.
  11. LATS2 expression differences in lung adenocarcinoma and lung squamous cell carcinoma analyzed using bioinformatics and experimental approaches.
  12. Clinical evaluation of ex vivo expanded MUC1-specific peripheral blood T Cells for adoptive immunotherapy in relapsed/refractory multiple myeloma.
  13. Computer Vision for Predicting the Efficacy of Neoadjuvant Therapy in Breast Cancer.
  14. Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
  15. Folate receptor beta targeting of tumor-associated macrophages improves lymphoma cell responses to CD19 CAR T cells.
  16. CXCL13-expressing CD4+ T cells coordinate the lymphocytes triad to promote the anti-tumor immunity in NSCLC.
  17. Preserved CD4 + T cell helper function and coordinated antiviral immunity in people with HBV/HIV co-infection on long-term therapy.
  18. Peptide-reactive T cell response as a novel biomarker in head and neck cancer patients treated with anti-PD-1 antibody.
  19. Nano-enabled strategies for enhancing cancer immunotherapy: challenges, progress and perspective.
  20. PD-1+CD8+ T cell infiltration complements PD-L1 to predict first-line chemo-immunotherapy outcomes in advanced ESCC.
  21. α-Galactosylceramide-expanded virtual memory CD8+ T cells confer protection against a broad range of pathogens.
  22. Beyond the chimeric antigen receptor T cells and bispecific antibody duopoly: ex vivo armed T cells for solid tumors.
  23. Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
  24. Longitudinal spatial neutrophil profiling during ACT in murine melanoma reveals distinct lymph node infiltration patterns.
  25. Immune Landscape and Tumour Heterogeneity in Ovarian Cancer: Insights From Single-Cell RNA Sequencing.
  26. HBV-driven expansion of CXCR6+-exhausted T cells and CXCL16+ macrophage interaction: Implications for immunotherapy in HCC.
  27. Giant Cell Urothelial Carcinoma: Morphometric Insights and Associations With Aggressive Clinical Features.
  28. Combined targeting of mesothelin and tenascin-C enhances CAR-T cell function and tumor microenvironment modulation in ovarian cancer.
  29. CCR5+ CD8+ T Cells Are Associated with Poor Response to PD-1 Blockade Therapy.
  30. Inducible T Cell Costimulator Ligand and Inducible T Cell Costimulator Stratification Identify Dichotomous Tumor Microenvironment and Guide Chemo-Immunotherapy in Small Cell Lung Cancer.
  31. Deep spatial proteomics reveals a suppressive immune niche linked to immune evasion in renal cell carcinoma.
  32. Immune Related Pathological Features and Predictive Score in Intrahepatic Cholangiocarcinoma Treated With Combined Conversion Immunotherapy.
  33. AI-based pathomics model predicts regulatory T cell infiltration and radiotherapy response in IDH-wild-type glioblastoma.
  34. Meaningful efficacy measures and trial endpoints in patients with advanced melanoma being considered for adjuvant systemic therapy: a prospective patient survey study.
  35. Progression risk among responders to PD-1/PD-L1 blockade is primarily stratified by response depth: A nationwide cohort study of 2127 patients with melanoma, RCC, and NSCLC.
  36. DNA hypomethylating agents preserve T cell stemness and potentiate the efficacy of CD3-bispecific antibodies.
  1. PeerJ. 2026 ;14 e20969
    Tumor infiltrating lymphocytes against solid tumors: current trends & perspectives.
    Ze Min Liew, Yu Shyan Low, Khang Chiang Oh, Qian Yue Lee, Gee Jun Tye, Richard Bayliss, Chun-Wai Mai, Michelle Yee Mun Teo, Lionel Lian Aun In.
      Tumor-infiltrating lymphocytes (TILs) are recognized as a key component of anticancer immunity and serve as an important prognostic factor in cancer progression. In this review, the latest updates and perspectives on the diverse populations of TILs and their roles in cancer immunity are discussed. The presence and balance between anti-tumorigenic and pro-tumorigenic immune cells in the tumor microenvironment (TME) largely determine tumor progression and fate. Thus, the properties of TILs were reviewed to provide a better insight into the roles of these immune cells within the TME. Additionally, the different factors influencing immune cell infiltration in solid tumors are also described to suggest novel immunotherapeutic approaches for improved TIL infiltration. These recent approaches are then summarised as recommendations to improve infiltration and potentially achieve better clinical outcomes. Overall, this review highlights the critical role of TILs, factors governing immune cell homing and infiltration, and strategic approaches to improve TIL infiltration.
    Keywords:  Chemokines; Immunotherapy; Solid tumor; Tumor immunology; Tumor infiltrating lymphocytes; Tumor microenvironment
    DOI:  https://doi.org/10.7717/peerj.20969
  2. Oncotarget. 2026 Jan 06. 17(1): 314-315
    Tumor infiltrating lymphocyte (TIL) therapy for treating the solid tumors: Challenges and future perspectives.
    Sharma Bhartendra, Kaur Sukhbir, Sharma Vikas, Soni Sanjay.
      
    Keywords:  adoptive cellular therapy; immunotherapy; solid tumors; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.18632/oncotarget.28883
  3. Cancer Immunol Res. 2026 Jun 08.
    ILT2 identifies an unexploited pool of intratumoral CD8+ bystander T cells with TCR-independent cytotoxicity in renal cell carcinoma.
    Rebecca Laboureur, Clément Dumont, Dzenis Koca, Leonard Lugand, Margaux Bossis, Emilie Artru, Alix Jacquier, Jerome Verine, Fatiha Bouhidel, Malika Djouadou, Alexandra Masson-Lecomte, Jules Russick, Edgardo D Carosella, François Desgrandchamps, Laurent Guyon, Pierre Tonnerre, Joel LeMaoult, Nathalie Rouas-Freiss.
      Immune checkpoint inhibitors (ICIs) have improved clear-cell renal cell carcinoma (ccRCC) therapy, yet many patients remain unresponsive. Alternative strategies are needed, and the HLA-G/ILT2 axis has emerged as a promising immunosuppressive pathway. Here, we deeply characterized CD8⁺ILT2⁺ tumor-infiltrating lymphocytes (TILs) as a distinct subset from CD8⁺PD1⁺ TILs in ccRCC, using high-dimensional spectral flow cytometry, single-cell transcriptomics, and TCR clonotype analysis. CD8⁺ILT2⁺ TILs were terminally differentiated, highly cytotoxic "bystander" cells, enriched for virus-specific TCRs. They phenotypically, transcriptionally and functionally mirrored their circulating counterparts, suggesting peripheral recruitment. In dynamic co-culture assays, they exhibited potent TCR-independent cytotoxicity, mediated by activating innate receptors, namely NKG2D. However, HLA-G inhibited this activity, underscoring the immune-evasive role of the HLA-G/ILT2 axis. Our study defines CD8⁺ILT2⁺ TILs as an untapped effector population with potential antitumor activity and a promising therapeutic target in ccRCC. These findings offer new insights into TIL functional diversity and pave the way for innovative immunotherapies beyond conventional ICIs.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1109
  4. J Dermatol. 2026 Jun 10.
    Phenotypic Analysis of 26 Cultured TILs Derived From Japanese Melanoma Tissues.
    Rena Oguma, Shigeru Koizumi, Yuka Saeki, Kazuhiro Aoyama, Yu Kawahara, Takamitsu Matsuzawa, Noriko Saito, Ayako Oikawa, Katsushige Kawase, Akiko Honobe-Tabuchi, Ryosuke Tagashira, Chie Urasaki, Yaei Togawa, Tatsuyoshi Kawamura, Toyoyuki Hanazawa, Shusuke Kawashima, Takashi Inozume.
       PURPOSE: Tumor-infiltrating lymphocyte (TIL) therapy has attracted increasing attention as a promising next-generation cancer immunotherapy that may overcome some limitations of current immune checkpoint inhibitors. However, the phenotypic characteristics and tumor reactivity of TILs derived from Japanese melanoma tissues remain insufficiently investigated. This study aimed to evaluate the feasibility of expanding TILs from Japanese melanoma specimens and to characterize their phenotype and autologous tumor reactivity.
    METHODS: TILs were expanded from 26 Japanese melanoma specimens, including tumors derived from primary and mucosal lesions. The phenotypes of cultured TILs were assessed, and reactivity against autologous tumor cells was evaluated in 9 available TIL samples.
    RESULTS: TILs were successfully expanded from Japanese melanoma tissues, consistent with previous reports from the United States. The phenotypes of cultured TILs varied substantially among cases. Among the 9 TIL samples tested for reactivity against autologous tumor cells, MHC class I-restricted specific reactivity was detected in 7 samples, including 1 sample derived from mucosal melanoma. No clear association was observed between autologous tumor reactivity and the proportion of CD3+CD8+ T cells or the expression of specific markers on CD3+CD8+ T cells.
    CONCLUSION: This study is the first to characterize cultured TILs established from a series of Japanese melanoma patients. These findings suggest that the expansion of tumor-reactive TILs from Japanese melanoma tissues is feasible and may provide a basis for the development of TIL therapy in Japan.
    Keywords:  CD8+ T cells; Japanese; TIL; autologous tumor reactivity; melanoma
    DOI:  https://doi.org/10.1111/1346-8138.70346
  5. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00588-7. [Epub ahead of print]45(6): 117510
    Peptide-MHC-targeted engineered virus-like particles enable selective priming and gene editing of tumor-specific T cells.
    Brian H Shim, Q Henry Zhao, Jack A Queenan, Blake E Smith, Michael E Birnbaum, David R Liu.
      Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific TILs ex vivo. Here, we present a strategy using engineered virus-like particles (eVLPs) pseudotyped with peptide-major histocompatibility complexes (pMHCs) as a programmable, single-effector platform for selective and coordinated priming, expansion, and genome editing of rare antigen-specific CD8+ T cells among their endogenous polyclonal repertoires. We demonstrate that pMHC-pseudotyped eVLPs (pMHC-eVLPs) deliver T cell function-enhancing base editors to arm polyclonal lymphocytes with enhanced anti-tumor cytotoxicity by selectively expanding and engineering the tumor-specific T cell compartment. Our work establishes pMHC-eVLPs as a platform for enhancing TIL therapy with precision gene edits without the risks of bystander T cell engineering associated with polyclonal TIL engineering approaches.
    Keywords:  CP: cancer; TIL therapy; gene editing; genomics; targeted delivery; virus-like particles
    DOI:  https://doi.org/10.1016/j.celrep.2026.117510
  6. Breast Cancer. 2026 Jun 12.
    Changes in CD8-positive lymphocytes following chemotherapy with concomitant bevacizumab in HER2-negative breast cancer.
    Eriko Narusawa, Ayaka Katayama, Yukio Koibuchi, Daisuke Takata, Chikako Kanno Honda, Sayaka Obayashi, Sasagu Kurozumi, Daisuke Takahari, Ken Shirabe.
       BACKGROUND: Bevacizumab is an anti-angiogenic agent that inhibits tumor vascularization and thereby suppresses tumor growth. Tumor-infiltrating lymphocytes (TILs), particularly CD8-positive TILs, play a critical role in the antitumor immune response. However, little is known about the effect of bevacizumab-containing chemotherapy on CD8-positive TIL dynamics. This study aimed to evaluate changes in CD8-positive TILs before and after treatment in patients with advanced breast cancer receiving bevacizumab in combination with chemotherapy.
    METHODS: Thirty patients with initially inoperable advanced breast cancer who responded to first-line bevacizumab-containing chemotherapy and subsequently became eligible for surgery were included. CD8-positive TILs were assessed by immunohistochemistry in biopsy samples obtained before treatment and in surgical specimens collected after treatment. Stromal CD8-positive TILs were classified as low, intermediate, or high, based on their proportion among total stromal TILs.
    RESULTS: Of the 30 patients, 20 had luminal-like breast cancer and 10 had triple-negative breast cancer. Before treatment, CD8-positive TIL expression was low in 16 patients (64.0%), intermediate in 6 (24.0%), and high in 3 (12.0%). After treatment, 10 patients (33.3%) showed low expression, 11 (36.7%) had intermediate expression, and 9 (30.0%) had high expression, indicating an increase in CD8-positive TIL levels. The high pathological response (a pathological response grade of 2 or higher) rate was 36.7%, and patients with increased CD8-positive TILs tended to show higher pathological response and better overall survival, although these differences did not reach statistical significance. In contrast, the ypT stage was significantly lower in cases with high post-treatment CD8-positive TIL expression, suggesting that immune activation after bevacizumab may contribute to local tumor regression.
    CONCLUSIONS: Bevacizumab-containing chemotherapy appears to enhance CD8-positive TIL infiltration in primary breast tumors, which may contribute to improved local tumor regression and better therapeutic outcomes.
    Keywords:  Bevacizumab; CD8; HER2 negative breast cancer; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s12282-026-01869-w
  7. Cancer Immunol Immunother. 2026 Jun 06.
    Immune-cold NSCLC tumors harbor tumor-associated macrophages with elevated expression of immunoglobulin genes.
    Markus Haug, Henrik Sahlin Pettersen, Magne Børset, Arne Kildahl-Andersen, Sissel Gyrid Freim Wahl, Arnar Flatberg, Anders Tøndell.
      In the non-small cell lung cancer (NSCLC) tumor microenvironment (TME), tumor cells mediate inhibitory signals to key immune cells, promoting an immunosuppressive environment that facilitates tumor immune evasion. CD8 + cytotoxic T lymphocytes are central mediators of antitumor immunity, and tumors can be classified by immunohistochemistry (IHC) as immune-hot or immune-cold based on the abundance of tumor-infiltrating lymphocytes (TILs). Although cancer immunotherapy can boost lymphocyte functions and improve progression-free survival in patients with advanced NSCLC, only a minority of patients experience a durable clinical benefit. Tumor-associated macrophages (TAMs) are key immunoregulatory cells in the NSCLC microenvironment and capable of generating potent immunosuppressive signals. However, their functional roles in immune-hot versus immune-cold tumors remain poorly understood. In this study, we compared the transcriptional programs of TAMs from NSCLC patients with immune-hot or immune-cold tumors. We classified 11 surgically resected NSCLC tumors as immune‑hot or immune‑cold based on quantitative immunohistochemistry of CD4⁺ and CD8⁺ tumor‑infiltrating lymphocytes. TAMs were isolated from tumor and adjacent healthy tissue by fluorescence-activated cell sorting (FACS), followed by bulk RNA sequencing and differential gene expression analysis. TAMs from immune‑cold tumors exhibited a striking upregulation of genes involved in immunoglobulin-mediated immune responses. Additionally, these TAMs demonstrated increased expression of genes involved in extracellular matrix organization, including matrix metalloproteinases and collagen‑associated genes, suggesting enhanced matrix remodeling activity. These findings highlight TAMs' potential contribution to immunosuppression, stromal remodeling, and impaired lymphocyte infiltration. The TAM-mediated pathways identified here may represent actionable targets for future immunotherapeutic strategies aimed at reshaping the tumor microenvironment.
    Keywords:  Immune response; Non-small cell lung cancer; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00262-026-04446-4
  8. Discov Oncol. 2026 Jun 10. pii: 896. [Epub ahead of print]17(1):
    A bibliometric analysis of global research trends in adoptive cell therapy for triple negative breast cancer over the past 15 years.
    Wesam Ibrahim Abo Elenien, Nada Ashraf Ibrahim, Mariam Mohamed, Youssef Abo Elenien, Momen Heiba, Osama Abouelenin, Dunya Abbas Mahmood, Farhan Khaleel Hussein.
       BACKGROUND: The aggressive and diverse subtype of breast cancer known as triple-negative breast cancer (TNBC) has poor clinical outcomes and few specific therapeutic choices. Tumor-infiltrating lymphocytes (TILs), T-cell receptor-engineered T cells, and chimeric antigen receptor T (CAR-T) cells are examples of adoptive cell therapy (ACT), which has become a promising immunotherapeutic approach. Its clinical application in TNBC is still difficult, nevertheless. This study used bibliometric techniques to thoroughly assess growing hotspots, intellectual structure, and worldwide research trends pertaining to ACT in TNBC.
    METHODS: The Scopus database was searched for publications related to ACT in TNBC from 2011 to 2025. There were only original articles and reviews written in English. VOSviewer (version 1.6.20) and Microsoft Excel 2021 were used to analyse bibliometric indicators, such as annual publication output, country and institutional contributions, authorship patterns, citation characteristics, and keyword co-occurrence. To investigate thematic evolution and collaboration patterns, network visualisation and clustering analysis were carried out.
    RESULTS: With a compound annual growth rate of more than 60%, a total of 8,496 publications were found, indicating an exponential rise in research output, especially beyond 2020. Together, China and the US accounted for over 60% of all publications, dominating the world's research output. The core research network was made up of a few institutions and very productive writers. CAR-T cell therapy, tumor microenvironment manipulation, immunological checkpoint inhibition, metabolic reprogramming, and biomarker-driven methods were among the clinically orientated themes that emerged from foundational and preclinical investigations, according to keyword analysis. The literature shows ongoing translational difficulties with regard to tumor heterogeneity, antigen instability, immunosuppressive microenvironments, and safety concerns in solid tumors, despite increased research activity.
    CONCLUSION: Over the past ten years, research on ACT in TNBC has grown significantly, reflecting both unmet clinical need and growing scientific interest. However, continuous efforts to overcome biological and translational constraints are highlighted by the concentration of scientific leadership and the conceptual move towards combination methods and next-generation engineering approaches. This bibliometric analysis offers a thorough picture of the state of the field and could direct future research, teamwork, and the creation of more potent ACT tactics for TNBC.
    Keywords:  Adoptive cell therapy; Bibliometric analysis; CAR-T cells; Immunotherapy; Triple-negative breast cancer; Tumor microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s12672-026-05277-6
  9. Clin Transl Oncol. 2026 Jun 08.
    SAFE-IOERT prospective study: clinical outcomes of exclusive intraoperative radiotherapy in early breast cancer according to molecular subtype and tumor-infiltrating lymphocytes.
    G Oses, C Clavell, B González-Farré, E Sanfeliu, M Laplana, A Martínez, S Moreno, G Meca, E Gomis, J Carreras-Ballvé, E Mension, I Cebrecos, X Caparrós, J Tarrats-Rosell, C Cases, A Herreros, M Mollà.
       PURPOSE AND OBJECTIVES: Intraoperative electron radiotherapy (IOERT) can be applied during breast conserving surgery to treat invasive breast cancer. Tumor-infiltrating lymphocytes (TILs) are fundamental elements of the specific immunological response against tumor cells and have prognostic importance in many types of cancer. The aim of the study was to analyze the local recurrence rate, adverse effects, surrogate molecular subtype, and stromal percentage of TILs in patients with breast cancer treated with exclusive IOERT.
    MATERIALS AND METHODS: Eighty-one patients with early-stage breast carcinoma were included in a prospective study and were treated performing a conservative surgery, followed by IOERT with a dose of 20 Gy as accelerated partial breast irradiation (APBI). TILs were evaluated in hematoxylin-eosin sections of surgical specimens before IOERT.
    RESULTS: The median follow-up of the patients was 58 months (range 15-128). Fifty-eight patients (71.6%) were classified as Luminal A-like, 21 patients (25.9%) Luminal B-like and 2 patients (2.5%) were classified as HER2 positive-like. The local recurrence rate was 2.5%. Two patients presented ipsilateral local recurrence, and one patient presented distant recurrence. Eight patients (9.9%) suffered chronic toxicity with grade 1 localized fibrosis, fat necrosis, and pain. Eighty-one percent of stromal TILs were low and 14.9% were intermediate. In 3 patients (4.1%) the stromal percentage of TILs could not be assessed.
    CONCLUSIONS: In this prospective cohort of carefully selected patients with early breast cancer, exclusive IOERT delivered as accelerated partial breast irradiation achieved favourable local control with minimal chronic toxicity. Predominantly low stromal TIL levels in luminal-like tumours may be associated with recurrence risk. Larger prospective studies are needed for validation.
    Keywords:  APBI; Adverse effects; Early breast cancer; IOERT; Local recurrence; TILs
    DOI:  https://doi.org/10.1007/s12094-026-04445-y
  10. Cancer Res Commun. 2026 Jun 12.
    Tobemstomig, a novel bispecific antibody, preferentially blocks PD-1 and LAG-3 on CD8 TILs to expand stem-like T-cells for sustained tumor control.
    Patrick A A Weber, Mario Perro, Valeria G Nicolini, Klas Hatje, Silvia Jenni, Stefanie Briner, Esther Bommer, Manuela Tanner, Sylvain Pilet, Tamara Hüsser, Emilio Yángüez, Stanford Chen, Antonio Peixoto, Iryna Dekhtiarenko, Laura Lauener, Sylvia Herter, Thomas Höfer, Carina Hage, Meher Majety, Marina Bacac, Sara Colombetti, Stephane Leclair, Stefan Seeber, Merlind Mücke, Pablo Umaña, Christian Klein, Laura Codarri Deak.
      Checkpoint inhibitors targeting PD-1 have shown unprecedented efficacy in some cancer patients; however, co-expression of the immune-checkpoint LAG-3 by tumor infiltrating lymphocytes (TILs) might hinder such efficacy. PD-1 and LAG-3 are established markers of T-cell exhaustion in cancer and are co-expressed by stem-like CD8 T cells, a population critical for the response to anti-PD1 therapy, providing the rationale for their dual-blockade. Yet, blocking LAG-3 can lead to the expansion of regulatory T cells, reducing the efficacy of anti-LAG-3 therapy on CD8 TILs. To address this limitation, we developed tobemstomig, a novel bispecific antibody to preferentially and simultaneously block PD-1 and LAG-3 in cis on tumor-specific CD8 TILs, while sparing Tregs. It provided superior tumor growth inhibition in mouse models by replenishing stem-like cells and cytotoxic effector CD8 TILs, resulting in durable responses compared to monospecific antibodies targeting PD-1 and LAG-3 separately, which eroded the stem-like T cell pool over time.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0207
  11. Oncol Lett. 2026 Jul;32(1): 316
    LATS2 expression differences in lung adenocarcinoma and lung squamous cell carcinoma analyzed using bioinformatics and experimental approaches.
    Zhen Zhang, Shaoyan Zhang, Yalai Xu, Changyu Zhang, Xudong Zhang.
      The present study aimed to investigate the role and expression of large tumor suppressor kinase 2 (LATS2) in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). The expression levels of LATS2 in LUAD and LUSC, as well as their association with clinical characteristics and patient survival, were analyzed using data obtained from The Cancer Genome Atlas. A total of 100 LATS2-related genes were screened to conduct Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses. The association between LATS2 expression and immune cell infiltration, particularly CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs), was analyzed. The role of LATS2 in tumor cells was validated by observing the changes in proliferation, apoptosis, migration and invasion of LUAD and LUSC cells following LATS2 overexpression. LATS2 expression was low in both LUAD and LUSC. In LUAD, high expression of LATS2 was associated with lymph node metastasis, distant metastasis and TNM stage and served as an independent risk factor for both overall survival and progression-free survival. Conversely, in LUSC, LATS2 exhibited a weak association with clinical characteristics and survival. In LUAD and LUSC, LATS2-related genes exhibited differences in their associated functional pathways and biological processes. In LUAD, LATS2 was positively associated with CD4+ TIL proportions and CD4+/CD8+ TIL proportions, while exhibiting a negative association with CD8+ TIL proportions. In LUSC, no such associations were observed. In vitro experiments demonstrated that overexpression of LATS2 inhibited proliferation, migration and invasion, while promoting apoptosis, in both LUAD and LUSC cell lines, with notably stronger effects observed in LUAD cells. In conclusion, LATS2 exerts tumor-suppressive functions in both LUAD and LUSC. In LUAD, LATS2 is an independent risk factor for patient survival, possibly due to its close association with CD8+ TIL levels; however, this relationship is not pronounced in LUSC.
    Keywords:  bioinformatics analysis; in vitro experiments; large tumor suppressor kinase 2; lung adenocarcinoma; lung squamous cell carcinoma; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3892/ol.2026.15671
  12. Cancer Res Commun. 2026 Jun 11.
    Clinical evaluation of ex vivo expanded MUC1-specific peripheral blood T Cells for adoptive immunotherapy in relapsed/refractory multiple myeloma.
    Erin W Meermeier, Dara S Missan, Latha B Pathangey, Caleb K Stein, Gabrielle A Reckard, Susie A Darvish, Gregory J Ahmann, Jill Adamski, Rafael Fonseca, Sandra J Gendler, Michael P Gustafson, P Leif Bergsagel.
       PURPOSE: Naturally occurring tumor-specific T cells derived from peripheral blood (PB) offer a clinically accessible source for adoptive immunotherapy. However, expansion of these T cells from cancer patients remains a challenge. We hypothesized that mimicking innate immune activation could optimally stimulate antigen-driven T cell expansion in vitro, unlocking the therapeutic potential of PB-derived T cells.
    EXPERIMENTAL DESIGN: We previously developed an ex vivo culture system that selectively expands tumor antigen-activated T cells from PB mononuclear cells (PBMCs), generating multiclonal effector and central memory T cells. In this hypothesis generating study, we evaluated the therapeutic potential of MUC1-activated T cells in patients with relapsed and/or refractory multiple myeloma (r/rMM) in a phase I clinical trial (NCT05411497). MUC1 is an oncoprotein overexpressed in r/rMM. We translated our small-scale culture into GMP-compliant, large-scale manufacturing which achieved expansion of T cells from heavily pre-treated patients' PBMCs without exhaustion. Five patients were treated with escalating doses of up to 1x10^10 T cells.
    RESULTS: While the cell infusions were well tolerated, no objective responses occurred. One patient, who received the highest dose, has had stable disease for two years post-infusion. This patient exhibited transient dermatitis with localized MUC1 and CD3 staining, as potential evidence of on-target, off-tumor T cell reactivity, perhaps contributing to disease stabilization. TCR sequencing revealed the T cell product in four of the patients' blood, which correlated with the product's degree of polyfunctionality and MUC1-reactivity.
    CONCLUSION/DISCUSSION: These findings demonstrate the feasibility, safety, and biological activity of PB-derived, MUC1-specific T cells as adoptive immunotherapy.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0713
  13. Cancers (Basel). 2026 Jun 05. pii: 1857. [Epub ahead of print]18(11):
    Computer Vision for Predicting the Efficacy of Neoadjuvant Therapy in Breast Cancer.
    Daria Sitnikova, Alexey Fayzullin, Fedor Chistov, Peter Timashev, Nikita Savelov.
      Neoadjuvant therapy (NAT) is a standard component of breast cancer treatment, yet response rates vary substantially across patients. Accurate prediction of pathological complete response remains an unmet clinical need to improve patient selection for NAT. This review summarizes current approaches of using computer vision to predict breast cancer response to NAT from histopathological slides. We examined studies employing computer vision and machine learning models on hematoxylin and eosin and immunohistochemically stained whole-slide images, focusing on morphological features of tumor cells, stroma and tumor-infiltrating lymphocytes associated with pathological complete response. Key morphological predictors of therapy resistance included low tumor cell density with cord-like patterns, necrosis, predominance of collagenous and fibroblast-rich stroma and tumor vascularization, while therapy sensitivity was associated with high nuclear staining intensity, high tumor cell density and lymphocyte infiltration. We highlighted the advantages of incorporating multimodal data to enhance predictive performance. Our analysis demonstrates that computer vision models can detect subtle morphological patterns that may be difficult for pathologists to evaluate, providing valuable insights for personalized therapy planning in breast cancer. Further development of cross-modal, interpretable artificial intelligence solutions may improve prediction accuracy and deepen our understanding of tumor biology relevant to NAT response.
    Keywords:  breast cancer; computer vision; digital pathology; neoadjuvant; pathological response
    DOI:  https://doi.org/10.3390/cancers18111857
  14. Sci Adv. 2026 Jun 12. 12(24): eaee0517
    Targeting TMED4 enhances CD8+ T cell function and CAR T cell efficacy in solid tumors through the IRE1α-autophagy axis.
    Huizi Wang, Licai Shi, Ke Jiang, Shuyao Wu, Zhenyan Jiang, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Sophia Jiaxin Wu, Guang Chen, Ming Qin, Lin Xu, Chu-Hu Lai, Alexandra Aicher, Youqiong Ye, Christopher Heeschen, Yu J Cao, Xuefeng Wu.
      Endoplasmic reticulum stress (ERS) and autophagy regulate tumor-infiltrating T cell function and exhaustion, but the underlying mechanisms remain unclear. Here, we identified the ERS-related transmembrane protein TMED4 (transmembrane emp24 domain-containing 4) as a critical regulator of CD8+ T cell antitumor immunity. Tmed4 deletion in T cells enhanced antitumor responses by promoting CD8+ T proliferation, infiltration, and killing capacity, while reducing terminal exhaustion. Mechanistically, Tmed4 deficiency hyperactivated the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis and induced autophagy flux in an IRE1α-dependent manner. Genetic deletion of Ern1 (IRE1α) or Becn1 (Beclin1) impaired the antitumor effects of Tmed4 deficiency, underscoring the role of ERS and autophagy in CD8+ T cell function. Moreover, Tmed4-deficient chimeric antigen receptor T cells (CAR T cells) displayed improved antitumor immunity. Pharmacological inhibition of Tmed4 using antisense oligonucleotide also enhanced CD8+ T cell-mediated tumor control. In summary, our study reveals that TMED4 governs CD8+ T cell effector function and limits terminal exhaustion through IRE1α-driven autophagy, establishing TMED4 as a promising immunotherapeutic target for improving CAR T cell efficacy.
    DOI:  https://doi.org/10.1126/sciadv.aee0517
  15. Hemasphere. 2026 Jun;10(6): e70390
    Folate receptor beta targeting of tumor-associated macrophages improves lymphoma cell responses to CD19 CAR T cells.
    Kerttu Kalander, Katri Oksa, Selma Sorri, Hector Monzo, Suvi-Katri Leivonen, Päivi M Ojala, Sirpa Leppä.
      Chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, approximately half of the patients experience lymphoma progression after CD19 CAR T cell therapy. Immunosuppressive, M2-like tumor-associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment (TME) and may facilitate resistance to CAR T cell therapy. Here, we identified folate receptor beta (FRβ) as a specific marker of M2-like TAMs and a predictor of poor survival in multiple independent DLBCL cohorts. Co-culture studies of lymphoma-macrophage spheroids revealed reciprocal interactions between lymphoma cells and M2-like macrophages. Lymphoma cell co-cultures promoted the differentiation of monocytes into M2-like macrophages, while M2-like macrophages fostered lymphoma cell growth and interfered with CD19 CAR T cell-mediated killing of lymphoma cells. We demonstrated that M2‑like macrophages drive CAR T cells toward an exhausted phenotype and validated this finding using data from patients treated with CD19 CAR T cell therapy. Lastly, we generated FRβ-targeting CAR T cells and used them prior to CD19 CAR T cells to successfully improve lymphoma cell killing. Taken together, the results suggest active crosstalk between lymphoma cells and M2-like macrophages, as well as TAM-mediated resistance mechanisms to CD19 CAR T cells, which can be circumvented by FRβ CAR T cells targeting the M2-like TAMs. These results support the use of macrophage-targeting to improve CAR T cell therapy outcomes in DLBCL.
    DOI:  https://doi.org/10.1002/hem3.70390
  16. Oncoimmunology. 2026 Dec 31. 15(1): 2684116
    CXCL13-expressing CD4+ T cells coordinate the lymphocytes triad to promote the anti-tumor immunity in NSCLC.
    Danping Liu, Jiajun Luo, Wei Guo, Junrui Ma, Xiaobao Yang, Yihan Xia, Pu Li, Dakang Xu, Zhidong Gu.
      CD4+ T cells are indispensable for CD8+ T cells-mediated anti-tumor immunity, while little is known about how CD4+ T cells coordinate with other cells to promote CD8+ T cells activity. In this study, by coupling single-cell RNA sequencing (scRNA-seq) with multiplex immunohistochemistry staining (mIHC), CXCL13-expressing CD4+ T cells were explored to recruit CXCR5+ B cells to form CXCL13+CD4+ T cells:: CXCR5+ B cells:: CD8+ T cells triad, promoting the anti-tumor immunity and heralding a favorable prognosis. A CXCL13-expressing subset of CD4+ T cells was identified to be associated with better prognosis and tumor-reactive hallmarks. The further cell types interaction analysis revealed a specific interaction between CXCL13+CD4+ T cells and CXCR5+ B cells in comparison with other cell types. The mIHC verified that an elevated level of CXCR5+ B cells infiltration in the proximity of CXCL13+CD4+ T cells. The subsequent Entropy analysis, which characterizes the colocalization among more than two cell types, was employed to reveal the spatial distribution pattern. The results revealed that CXCL13+CD4+ T cells and CXCR5+ B cells co-localized with cytotoxic CD8+ T cells, forming a functional lymphocyte triad, whose existence heralded a better prognosis. Collectively, by integrating scRNA-seq with mIHC, we demonstrated that the recruitment of CXCR5+ B cells by neoantigen reacting to CXCL13+CD4+ T cells through CXCL13-CXCR5 signaling contributed to the lymphocyte triad, leading to an enhanced anti-tumor immunity and heralding a favorable prognosis in non-small-cell lung cancer (NSCLC).
    Keywords:  CXCL13+CD4+ T cells; CXCL13–CXCR5; NSCLC; lymphocytes triad; spatial analysis
    DOI:  https://doi.org/10.1080/2162402X.2026.2684116
  17. bioRxiv. 2026 Jun 05. pii: 2026.06.04.730166. [Epub ahead of print]
    Preserved CD4 + T cell helper function and coordinated antiviral immunity in people with HBV/HIV co-infection on long-term therapy.
    Aljawharah Alrubayyi, Anucha Preechanukul, Yinru Zhang, Jonida Kokici, Tanu Kamat, Jessica Davies, Indrajit Ghosh, Fiona Burns, Sabine Kinloch, Pedro Simoes, Sanjay Bhagani, Patrick T F Kennedy, Mala K Maini, Upkar S Gill, Dimitra Peppa.
       Background & Aims: People with HBV/HIV co-infection on antiretroviral therapy achieve higher rates of HBV functional cure than those with HBV mono-infection, yet the immunological basis remains poorly characterised. HBV-specific CD4 + T cell responses are critical for viral control and functional cure but have been scarcely examined in HBV/HIV co-infection. Our previous studies in HBV/HIV co-infection demonstrated preserved stem-like CD8 + T cells and NK cell functional responses, but whether CD4 + T cell helper function is similarly maintained is unknown.
    Methods: We analysed CD4 + T cell responses in 72 participants (HBV n=26, HBV/HIV n=24, HIV n=22) on suppressive antiviral therapy, using multiparameter flow cytometry, virus-specific CD4 + T cell functional assays and proliferation assays.
    Results: People with HBV/HIV co-infection had significantly higher HBV envelope- and core-specific CD4 + T cell responses, with IL-2 production particularly discriminating between groups. CD4 + T cell responses to CEF (CMV, EBV, and Influenza) were comparable, confirming antigen specificity. Granzyme B-expressing cytotoxic CD4 + T cells and TCF-1 + CD127 + PD-1 + CD4 + T cells were enriched in co-infection. CD4 + and CD8 + T cell responses were more frequently coordinated within donors in co-infection than in mono-infection (envelope 83% vs 50%; core 94% vs 60%), where they were more often uncoupled. IL-2 producing CD4 + T cells correlated with CD8 + T cell responses and the CD4:CD8 ratio in co-infection. HBV-specific proliferative capacity was enhanced in co-infection.
    Conclusions: People with HBV/HIV co-infection mount functional HBV-specific CD4 + T helper responses that are coordinated with CD8 + T cell immunity at the individual level. Together with our prior findings of preserved NK and CD8 + T cell responses in this cohort, these data identify treated HBV/HIV co-infection as a setting of integrated, rather than compromised, antiviral immunity.
    Impact and Implications: People with HBV/HIV co-infection can achieve HBV functional cure more frequently than people with HBV mono-infection, but the immune mechanisms remain unclear. This study shows that treated HBV/HIV co-infection is characterised by functional HBV-specific CD4⁺ helper responses and coordinated CD4⁺/CD8⁺ antiviral immunity. These responses were most strongly associated with the CD4:CD8 ratio, a routinely available clinical marker, rather than with CD4 count alone. These findings argue that people with HBV/HIV co-infection should be prioritised in, not excluded from, HBV cure immunotherapy trials.
    DOI:  https://doi.org/10.64898/2026.06.04.730166
  18. Cancer Res Commun. 2026 Jun 10.
    Peptide-reactive T cell response as a novel biomarker in head and neck cancer patients treated with anti-PD-1 antibody.
    Takumi Kumai, Shota Sakaue, Hisataka Ominato, Takahiro Inoue, Ryosuke Sato, Risa Wakisaka, Hiroki Komatsuda, Ryusuke Hayashi, Michihisa Kono, Hidekiyo Yamaki, Kenzo Ohara, Kan Kishibe, Miki Takahara.
      Immune checkpoint inhibitors (ICIs) have improved outcomes in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), yet reliable biomarkers predicting response to PD-1 blockade remain limited. We retrospectively analyzed 40 patients with R/M HNSCC treated with nivolumab or pembrolizumab monotherapy, evaluating clinical data, laboratory parameters, PD-L1 expression, tumor-infiltrating T cells, and peripheral immune features. Peripheral blood mononuclear cells obtained before treatment were assessed using flow cytometry for exhaustion markers and short-term tumor antigen-derived peptide stimulation with IFN-γ ELISA. The objective response rate was 18%, with median overall survival of 13 months and progression-free survival of 3 months. PD-L1 expression and densities of CD4⁺, CD8⁺, and FoxP3⁺ T cells were not associated with response. In contrast, responders more frequently developed immune-related adverse events and had preserved cervical lymph nodes. Favorable responses were associated with higher baseline lymphocyte and lower neutrophil percentages, as well as lower frequencies of CD38⁺ CD8⁺ T cells. Notably, c-Met-derived peptide stimulation induced significantly higher IFN-γ production in responders, indicating the presence of circulating tumor antigen-reactive T cells. These findings suggest that tumor antigen-reactive T cells, together with a favorable systemic immune profile, are associated with clinical benefit from PD-1 blockade, and that peripheral blood-based peptide-reactive T-cell assays may provide a practical approach for biomarker development in R/M HNSCC.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0796
  19. Immunopharmacol Immunotoxicol. 2026 Jun 09. 1-26
    Nano-enabled strategies for enhancing cancer immunotherapy: challenges, progress and perspective.
    Hazem Mathkour.
       OBJECTIVE: To review the role of nanotechnology in enhancing cancer immunotherapy, particularly immune checkpoint blockade (ICB), adoptive cell therapy (ACT), and cancer vaccines. It addresses key challenges in solid tumors, including poor drug delivery, immunosuppressive tumor microenvironment (TME), immune resistance, and treatment-related toxicity.
    METHODS: A narrative review of recent preclinical and clinical studies was conducted to evaluate how nanoplatforms improve targeted delivery, modulate the TME, enhance immune activation, and support immunotherapeutic efficacy. Challenges related to biosafety, biodistribution, scalability, and clinical translation were also discussed.
    RESULTS: Current findings demonstrate that nanotechnology-based platforms can significantly improve cancer immunotherapy outcomes. Nanomedicines enhance ICB by increasing intratumoral drug accumulation and reversing immune suppression within the TME. In ACT, nanoplatforms improve T cell persistence, function, and tumor infiltration. Nanoformulations also strengthen cancer vaccines through more efficient antigen delivery and enhanced antigen presentation.
    CONCLUSION: Preclinical and early clinical studies suggest that nano-immunotherapies can overcome important biological barriers and enhance antitumor immune responses while reducing systemic toxicity.
    DISCUSSION: Overall, nano-immunotherapy represents a promising strategy for improving the efficacy of cancer immunotherapy, particularly in solid tumors. Despite progress, several challenges remain, including long-term safety concerns, variability in nanoparticle design, manufacturing scalability, regulatory issues, and limited clinical data. Further researches are needed to optimize delivery systems, ensure safety, and facilitate successful clinical translation toward more effective and personalized cancer treatments.
    Keywords:  Cell therapy; combination therpy; nanovaccine; neoantigen; targeted agent
    DOI:  https://doi.org/10.1080/08923973.2026.2673541
  20. Biomark Res. 2026 Jun 08. pii: 61. [Epub ahead of print]14(1):
    PD-1+CD8+ T cell infiltration complements PD-L1 to predict first-line chemo-immunotherapy outcomes in advanced ESCC.
    Qian Zhao, Shuping Cheng, Yuliang Meng, Butuo Li, Linlin Wang.
      Only a subset of patients with esophageal squamous cell carcinoma (ESCC) benefits from first-line immunochemotherapy, and PD-L1 alone has limited predictive value, underscoring the need for complementary biomarkers. We analyzed pretreatment FFPE biopsies from 147 ESCC patients treated with PD-1 inhibitors plus chemotherapy using multiplex immunofluorescence (CD4, CD8, CD20, CD68, PD-1, PD-L1, DAPI). PFS and OS were assessed by Kaplan-Meier and Cox models; cut-offs were derived by ROC/Youden analyses. With a median follow-up of 32.2 months, median PFS and OS were 6.7 and 17.0 months. PD-L1 was predominantly expressed on tumor cells, whereas PD-1 was localized mainly to tumor-infiltrating immune cells. In multivariable analysis, high PD-L1 expression independently associated with longer PFS (HR 0.210, 95%CI: 0.060-0.731; p = 0.014), whereas high PD-1+CD8+ T cell infiltration predicted shorter PFS (HR 2.694, 95%CI: 1.162-6.246; p = 0.021). Combined stratification identified the longest PFS in high PD-L1 expression and low PD-1+CD8+ T cell infiltration (8.8 months) and the shortest in low PD-L1 and high PD-1+CD8+ T cell infiltration (3.5 months), supporting PD-1+CD8+ T cell infiltration might as a complementary biomarker to PD-L1. For OS, intratumoral CD8+ T cell density (HR 0.896; p = 0.011), clinical stage (HR 1.570; p = 0.025), and BMI (HR 0.935; p = 0.015) were independent factors.
    Keywords:  ESCC; Immunotherapy; Multiplex immunofluorescence; PD-1; Predict
    DOI:  https://doi.org/10.1186/s40364-026-00934-y
  21. Front Immunol. 2026 ;17 1799271
    α-Galactosylceramide-expanded virtual memory CD8+ T cells confer protection against a broad range of pathogens.
    Jia-Xun Xie, Dong-Lin Li, Meng-Chih Lai, Yu-Ling Su, Chi Tai, Ching-Chun Wang, Jr-Shiuan Lin.
      α-Galactosylceramide (α-GalCer) treatment of animals is a well-established model to investigate the beneficial roles of invariant natural killer T (iNKT) cells in anti-infection and anti-tumor immunity. We previously found that α-GalCer treatment expands not only iNKT cells but also a group of antigen-inexperienced memory-like innate virtual memory CD8+ T (CD8+ TVM) cells. With the bystander protective potential of CD8+ TVM cells, their roles in α-GalCer-mediated immunity against infection remain largely unexplored. Here, we reported that α-GalCer treatment conferred protection against systemic, enteric, and pulmonary bacterial infections, as well as pulmonary viral infection. This protection persisted after iNKT cells had diminished and coincided with sustained expansion of CD8+ TVM cells. Adoptive transfer of α-GalCer-expanded CD8+ TVM cells one day before infection significantly decreased bacterial and viral burdens. Mechanistically, α-GalCer treatment activated iNKT cells to produce IL-4, which subsequently expanded the number of CD8+ TVM cells that were capable of producing TNF-α and IFN-γ. But the ability of each individual CD8+ TVM cell to produce these cytokines was not enhanced. Lung-localized CD8+ TVM cells were the primary contributors to α-GalCer-expanded CD8+ TVM cells in the lung. α-GalCer-expanded CD8+ TVM cells can reduce pulmonary viral titer in the host in a TNF-α-dependent manner in the absence of IFN-γ signaling. Together, these findings describe an immune cascade in which α-GalCer-activated iNKT cells orchestrate the expansion and function of CD8+ TVM cells through IL-4 production, reveal previously unrecognized roles of CD8+ TVM cells as downstream effectors in α-GalCer-mediated immunotherapeutic effects, and highlight the protective potential of CD8+ TVM cells in host defense against diverse pathogens, thus providing a novel approach to developing new therapeutics for combating not only various infectious diseases but also tumors.
    Keywords:  IFN-γ; IL-4; TNF-α; enteric infection; pulmonary infection; systemic infection; virtual memory CD8+ T cells; α-Galactosylceramide
    DOI:  https://doi.org/10.3389/fimmu.2026.1799271
  22. Front Immunol. 2026 ;17 1822523
    Beyond the chimeric antigen receptor T cells and bispecific antibody duopoly: ex vivo armed T cells for solid tumors.
    Jeong A Park, Nai-Kong V Cheung.
      While monoclonal antibodies (mAbs) continue to dominate the overall immunotherapy landscape, the field of T-cell-based therapeutics is rapidly evolving. Although chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs) currently represent the pillars of T-cell-directed therapy, the complexity of solid tumors demands a more diversified therapeutic arsenal. By combining antibody-mediated tumor targeting with the robust effector function of ex vivo expanded T cells, BsAb-armed T cells (BATs)-also referred to as Ex vivo Armed T cell (EATs)-provide a 'third way' that addresses the unmet needs of solid tumor immunotherapy. They can overcome the quantitative and qualitative deficiencies of endogenous immune effector cells in cancer patients. By offering personalized multi-antigen targetability and the prospect of off-the-shelf therapy, EATs have the potential to address critical challenges, such as poor tumor infiltration, immune escape via heterogeneity and target antigen loss, and treatment-related toxicities like cytokine release syndrome. In this review, we discuss the characteristics of EAT therapy, distinct from CAR-T and BsAb therapy, as an independent and alternative niche. We explore strategies to accelerate their clinical translation, encompassing BsAb optimization, modulation of the tumor microenvironment (TME) and cytokines, and simultaneous engagement of multiple antigens, which are essential for boosting EAT potency and overcoming the limitations of solid tumors. In this evolving landscape, EATs could play a unique and independent role, expanding the CAR-T and BsAb-dominated paradigm to address unmet clinical needs.
    Keywords:  T cell immunotherapy; bispecific antibody; chimeric antigen receptor T cell; ex vivo armed T cell; multi-antigen targeting strategy; on-target off-tumor toxicity; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1822523
  23. bioRxiv. 2026 Jun 02. pii: 2026.05.28.728555. [Epub ahead of print]
    Critical illness expands a transcriptionally distinct hypometabolic CD8 + T effector program associated with respiratory failure and mortality.
    Casey M Nichols, Erin L Mwizerwa, Chooi Ying Sim, Sarah N Obeidalla, Jacqueline-Yvonne Cephus, Caroline E Roe, Jonathon M Irish, Dawn C Newcomb, V Eric Kerchberger, Julie A Bastarache, Jeffrey C Rathmell, Lorraine B Ware, Matthew T Stier.
      Immune dysfunction is a major driver of morbidity and mortality in critical illness syndromes including sepsis. Specifically, CD8 + T cell dysfunction has been linked to organ failure and death. To characterize the immune substructure of circulating CD8 + T cells in critical illness at high dimension, we used single-cell RNA sequencing of peripheral blood CD8 + T cells from 38 critically ill patients and 9 healthy controls. We annotated seven CD8 + T cell clusters, which included a CD8 + effector subset, termed T effector state 2 (T Eff-2 ), that was only present in critically ill patients and associated with more severe respiratory failure and higher mortality. T Eff-2 showed effector activation and inflammatory stress conditioning yet had markedly reduced metabolic transcripts without canonical features of exhaustion. Trajectory analyses positioned T Eff-2 as a terminal CD8 + T effector cell fate driven in part by DDIT4 and DUSP1 , which negatively regulate mTOR and MAPK signaling, respectively. Interestingly, this transcriptional program was indistinguishable by classical protein cytometry methods. These results, including the mortality association, were validated in a larger (n=91) independent external cohort of critically ill patients with sepsis. In summary, T Eff-2 represents a latent transcriptional program that delineates a clinically high-risk CD8 + T cell state in critical illness.
    DOI:  https://doi.org/10.64898/2026.05.28.728555
  24. NPJ Syst Biol Appl. 2026 Jun 11. pii: 84. [Epub ahead of print]12(1):
    Longitudinal spatial neutrophil profiling during ACT in murine melanoma reveals distinct lymph node infiltration patterns.
    Gemma van der Voort, Maike Effern, Michelle C R Yong, Lukas Kiwitz, Roberta Turiello, Sonia Leonardelli, Susanna Ng, Dillon Corvino, Tobias Bald, Nicole Glodde, Kevin Thurley, Jan Hasenauer, Michael Hölzel.
      Reactive neutrophil infiltration can restrain CD8+ T cell expansion in lymph nodes during adoptive T cell therapy (ACT), yet its spatiotemporal regulation remains incompletely understood. Levaraging flow cytometry and multiplex immunofluorescence data, we performed a time-resolved quantitative assessment of immune cell dynamics in tumor-draining lymph node (tdLN) and non-tumor-draining lymph node (non-tdLN) in a melanoma mouse model receiving ACT. Transferred tumor-reactive CD8+ T cells accumulated and expanded early after treatment initiation, showing the highest frequency of a favorable central memory 13 CD8+ T cell phenotype in the tdLN. Enhancing innate immune signaling in melanomas increased neutrophil influx into lymph nodes, particularly the non-tdLN; however, within the tdLN, neutrophils were enriched in the T cell zone, which also contained the largest absolute reservoir of transferred CD8+ T cells. Together, these findings indicate that tdLN and non-tdLN differ in early neutrophil dynamics and compartmentalization during ACT, influenced by the strength of innate immune signaling in the tumor.
    DOI:  https://doi.org/10.1038/s41540-026-00765-5
  25. J Cell Mol Med. 2026 Jun;30(11): e71235
    Immune Landscape and Tumour Heterogeneity in Ovarian Cancer: Insights From Single-Cell RNA Sequencing.
    Sihan Chen, Ghada Moh Samir Elhessewi, Helen Cai, Wedad M Alawad, Manoj Kumar Mishra, Usamah Sayed.
      Tumour heterogeneity is a key factor in cancer progression, with immune responses within the tumour microenvironment (TME) contributing significantly to treatment resistance and immunotherapy outcomes. Recent advances in single-cell RNA sequencing (scRNA-seq) have provided unprecedented insights into the diverse immune cell populations infiltrating tumours, including both innate immune cells like dendritic cells, neutrophils, macrophages, and natural killer (NK) cells, as well as adaptive immune cells such as T lymphocytes. The immune landscape of tumours is complex and dynamic, characterised by a mixture of activated and suppressed immune states that evolve over time. The degree of immune cell infiltration varies among tumour types and disease stages, influencing tumour response to therapies. For example, ovarian cancer typically exhibits weaker immune infiltration compared to cancers like melanoma and non-small cell lung cancer. Increased CD8+ T cell infiltration is generally associated with favourable prognosis, while elevated regulatory T cells (Tregs) can suppress anti-tumour immune responses. The use of scRNA-seq has enabled detailed profiling of immune cells, revealing the roles of exhausted T cells and immunosuppressive macrophages in the TME. This high resolution approach facilitates the identification of distinct immune cell subsets and their functional states, providing a platform for developing more targeted, personalised immunotherapies. The findings offer promising avenues for improving clinical outcomes in ovarian cancer and other malignancies through refined immune profiling.
    Keywords:  Bioinformatics; immune heterogeneity; immunotherapy; ovarian cancer; single‐cell RNA sequencing; tumour microenvironment
    DOI:  https://doi.org/10.1111/jcmm.71235
  26. Innovation (Camb). 2026 Jun 01. 7(6): 101274
    HBV-driven expansion of CXCR6+-exhausted T cells and CXCL16+ macrophage interaction: Implications for immunotherapy in HCC.
    Ranzhiqiang Yang, Congyu Lu, Qian Jian, Yinghui Song, Bo Sun, Wei He, Jieqiong Li, Fan Yang, Xiaohui Wang, Zhiguo Tan, Jiajin Yang, Chunzhao Yu, Chuang Peng, Yulong Yin, Yuan Gao, Liuqin He, Lianhong Zou, Sulai Liu.
      Hepatitis B virus (HBV) may alter immunotherapy responsiveness in HBV-positive hepatocellular carcinoma (HCC) patients. However, the underlying immune mechanisms remain unclear. To characterize the immune determinants underlying the enhanced immunotherapy response observed in HBV+ HCC patients, we comprehensively analyzed 528 HCC patients who received immunotherapy, encompassing diverse hepatitis infections. We performed an analysis incorporating single-cell RNA sequencing, spatial transcriptomics, and tissue microarray validation to map the tumor immune landscape. An adoptive T cell transfer combined with anti-programmed death-1 (PD-1) therapy in a syngeneic HCC mouse model was performed to validate key findings. HBV+ HCC patients exhibited superior responses to immunotherapy and prolonged overall survival. Remarkably, HBV+ HCC patients harbored an elevated proportion of exhausted CD8+ T cells, and these cells concurrently exhibited enhanced immune activity and cytotoxic potential. Our study spotlighted a novel subset of exhausted CD8+ T cells, termed PD-1+ CXCR6+ CD8+ T cells. In untreated cases, high levels of PD-1+ CXCR6+ CD8+ T cells correlated with poor prognosis. In contrast, among patients receiving immunotherapy, their enrichment was associated with markedly better outcomes. In vivo, adoptive transfer of CXCR6+ T cells markedly augmented the antitumor efficacy of anti-PD-1 therapy. Moreover, PD-1+ CXCR6+ CD8+ T cells demonstrated a prominent interaction with CXCL16+ macrophages in HBV+ HCC. Taken together, we identified a novel exhausted T cell subset, PD-1+ CXCR6+ CD8+ T cells, that are enriched in HBV+ HCC patients and maintained by CXCL16+ macrophages. The enrichment of PD-1+ CXCR6+ CD8+ T cells and their interaction with CXCL16+ macrophages may contribute to the enhanced immunotherapy response observed in HBV+ HCC.
    Keywords:  exhausted T cells; hepatitis virus; hepatocellular carcinoma; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xinn.2026.101274
  27. Am J Surg Pathol. 2026 Jun 08.
    Giant Cell Urothelial Carcinoma: Morphometric Insights and Associations With Aggressive Clinical Features.
    Huili Li, Amir Akbari, Matthew Schuler, Rodrigo Salgado Esteves, Kenneth J Pienta, Burles A Johnson, Ezra Baraban, Andres Matoso.
      Giant cell urothelial carcinoma (GCUC) is an exceedingly rare histologic subtype with 50+ reported cases. To date, 3 case series have been reported. Scant chemotherapy and immunotherapy responses were reported with variable results. We report the largest GCUC series, including 27 GCUC and 27 matched control urothelial carcinoma (CoUC) patients, most (>90%) of whom had more than 5 years of follow-up, including neoadjuvant and adjuvant therapy status. We further characterized the nuclear size ratio of giant tumor cells to background tumor cells and analyzed urothelial differentiation markers (GATA3, CK5/6), p53, tumor-infiltrating lymphocytes (CD19 and CD3), and therapeutic targets (TROP2, Nectin4, PDL1, and HER2). Morphometric analysis of giant tumor cells demonstrated that they were, on average, 12 times larger than surrounding nongiant tumor cells. GCUC showed many histologic and immunophenotypic features similar to CoUC. GCUC was enriched for higher stages (T3/4 and metastatic disease) than CoUC and showed a trend toward worse OS than conventional urothelial carcinoma, but was similar to urothelial carcinoma with variant histology. GCUC included 3 low-stage (T1/2) patients, who had significantly worse OS than low-stage CoUC, suggesting early extensive workup and oncologic intervention. Chemotherapy slightly improved OS in both GCUC and CoUC patients without statistical significance. Compared with CoUC, GCUC appeared to have more tumor-infiltrating T cells, but without statistical significance. There were no expression differences in TROP2, Nectin4, PDL1, and HER2. However, a subset of GCUC patients might benefit from target therapies (PDL1, Nectin4), warranting more cohort studies.
    Keywords:  PDL1; TROP2; giant cell urothelial carcinoma; nectin-4; survival
    DOI:  https://doi.org/10.1097/PAS.0000000000002576
  28. Mol Immunol. 2026 Jun 08. pii: S0161-5890(26)00129-X. [Epub ahead of print]196 35-43
    Combined targeting of mesothelin and tenascin-C enhances CAR-T cell function and tumor microenvironment modulation in ovarian cancer.
    Xiaoqin Wang, Duoyi Zhang, Tingting Wang, Xin Li, Jing Zhang.
       BACKGROUND: The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by dense extracellular matrix deposition and an immunosuppressive tumor microenvironment. Tenascin-C (TNC), an extracellular matrix protein enriched in ovarian cancer stroma, may provide a stromal cue that restricts T-cell engagement while offering a complementary target to mesothelin (MSLN). This study evaluated whether combined targeting of MSLN and TNC could enhance CAR-T-cell function and remodel the ovarian cancer microenvironment.
    METHODS: CAR-T cells targeting MSLN and/or TNC were generated using single lentiviral vectors encoding second-generation CAR constructs, including tandem dual-target CARs and MSLN-directed CAR-T cells secreting an anti-TNC single-chain variable fragment with or without a membrane-tethered PD-L1-binding module. CAR expression and function were evaluated across three healthy-donor batches. Target expression on SKOV3 cells and ovarian cancer-associated fibroblasts (CAFs) was validated by flow cytometry and qPCR. Functional studies included NFAT reporter assays, cytokine release, cytotoxicity, immune synapse quantification, adhesion assays, CAF co-culture, and xenograft studies with randomized treatment allocation and blinded tumor measurements.
    RESULTS: Dual-target TNC+MSLN CAR-T cells demonstrated reproducible CAR expression across donors, enhanced NFAT activation in TNC-rich conditions, increased CD69/CD25 upregulation, and greater IFN-γ, TNF-α, and IL-2 secretion than single-target controls. Compared with MSLN-CAR-T cells, dual-target CAR-T cells showed improved tumor-cell killing, larger and more polarized immune synapses, and stronger tumor-cell adhesion. In CAF co-culture, anti-TNC-secreting CAR-T cells partially reversed suppression, reduced PD-1 and Tim-3 expression, and showed concordant reductions in LAG-3 and TIGIT in exploratory analyses. In vivo, combination stromal targeting delayed tumor growth, increased intratumoral CD4 + and CD8 + infiltration, improved CAR-T persistence, and reduced extracellular matrix deposition and CAF-associated markers.
    CONCLUSIONS: Combined targeting of MSLN and TNC was associated with improved CAR-T-cell activation and broader microenvironmental remodeling in ovarian cancer models. These data support further evaluation of stromal co-targeting as an adjunct strategy for CAR-T therapy in ovarian cancer, while additional validation of target dependence, safety, and long-term persistence remains necessary.
    Keywords:  CAR-T; Mesothelin; Ovarian cancer; Tenascin-C; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molimm.2026.05.010
  29. Int J Mol Sci. 2026 May 30. pii: 4963. [Epub ahead of print]27(11):
    CCR5+ CD8+ T Cells Are Associated with Poor Response to PD-1 Blockade Therapy.
    Ziheng Zhao, Yuwei Liu, Zhaofei Wu, Chunliang Qi, Yingze Ning, Yiting Lin, Xuewen Pang, Guangliang Qiang, Wei Wang.
      Many patients develop poor clinical response to immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockade. However, transcriptomic features of chemokine receptors associated with poor response remain incompletely characterized. We analyzed publicly available single-cell RNA sequencing datasets from non-small-cell lung cancer (NSCLC) and melanoma cohorts, with additional exploratory analyses in hepatocellular carcinoma (HCC) and colorectal cancer datasets. Chemokine receptor expression on CD8+ T cells from clinical responsive and non-responsive samples to anti-PD-1 therapy was systematically profiled. Differential gene expression, cell-state scoring, pseudotime trajectory inference, and ligand-receptor interaction analysis were performed to characterize associated transcriptional states and predicted cellular interactions. CCR5 transcript expression in tumor-infiltrating CD8+ T cells was associated with lower responsiveness to PD-1/PD-L1 blockade therapy. CCR5+ CD8+ T cells exhibited transcriptional features associated with increased exhaustion, reduced stemness, and advanced differentiation. Pseudotime inference suggested progressively increased CCR5 expression along the inferred differentiation trajectory. Ligand-receptor interaction analysis further identified predicted interactions between CCR5+ CD8+ T cells and tumor-associated myeloid cells, with elevated expression of CCL3 and CCL4 observed in myeloid populations from non-responsive tumors. Together, these findings identify transcriptomic associations between CCR5+ CD8+ T cell states and poor clinical response to PD-1 blockade therapy. These observations support the CCL3/4-CCR5 axis as a candidate pathway for future spatial, functional, and experimental validation.
    Keywords:  CCR5; CD8+ T cells; PD-1 blockade therapy; exhaustion
    DOI:  https://doi.org/10.3390/ijms27114963
  30. MedComm (2020). 2026 Jun;7(6): e70782
    Inducible T Cell Costimulator Ligand and Inducible T Cell Costimulator Stratification Identify Dichotomous Tumor Microenvironment and Guide Chemo-Immunotherapy in Small Cell Lung Cancer.
    Qiji Guo, Yan Chen, Jijun Sun, Hongyi Zhang, Shuyu Ji, Huansha Yu, Lele Zhang, Haiyang Hu, Peng Zhang, Jing Zhang.
      Inducible T cell costimulator ligand (ICOSLG) regulates T cell functional states, yet its role in small cell lung cancer (SCLC) remains poorly characterized. By integrating multiple cohorts, we found that high tumor-intrinsic ICOSLG was associated with poor overall survival (OS) in the TU-SCLC cohort (p = 0.010) and the Wang et al. cohort (p < 0.001), and was associated with inferior efficacy to chemo-immunotherapy (hazard ratio [HR] = 2.66, p = 0.008). Consistently, the ICOSLG high subgroup exhibited significantly reduced functional CD8+ T cell infiltration, elevated exhausted CD8+ T cells, decreased effector molecules such as GZMK and IFNG, and enrichment of malignant pathways, including hypoxia, epithelial-mesenchymal transition, and others. Meanwhile, the correlation between ICOSLG and NEUROD1 expression was observed. On the contrary the subgroup high in ICOS, the main ICOSLG receptor, harbored NOTCH pathway mutations, showed an inflamed tumor microenvironment, better prognosis, and prolonged OS with chemo-immunotherapy (HR = 0.52, p = 0.003). Dual ICOSLG and ICOS stratification revealed that the ICOSLG low and ICOS high subgroup derived the greatest benefit from chemo-immunotherapy (median OS: 17.2 vs. 9.8 months; p < 0.001). Collectively, this dual-stratification strategy refined patient selection for chemo-immunotherapy, unveiled actionable targets, and ultimately advanced precision immunotherapy in SCLC.
    Keywords:  biomarkers; immunohistochemistry; immunotherapy; small cell lung cancer; translational medical research
    DOI:  https://doi.org/10.1002/mco2.70782
  31. Cancer Drug Resist. 2026 ;9 19
    Deep spatial proteomics reveals a suppressive immune niche linked to immune evasion in renal cell carcinoma.
    Yujia Zhang, Yicheng Zhu, Zichang Liu, Haonan Li, Bingxu Zhong, Xingang Cui, Yan Kong, Hui Lu.
      Aim: Clear cell renal cell carcinoma (ccRCC) presents an "immune paradox" where high CD8+ T cell infiltration correlates with poor survival and limited response to immune checkpoint blockade (ICB). Simple cell density metrics fail to capture the functional state of the immune microenvironment, suggesting an uncharacterized spatial mechanism underlying immune evasion and poor clinical outcomes. We aimed to develop an AI-driven spatial proteomics framework to decode this immunosuppressive phenotype. Methods: We developed PhenoSSP, a hierarchical deep learning framework based on a Vision Transformer backbone, designed for single-cell phenotyping from 7-channel multiplex immunofluorescence (mIF) images. It was applied to 1,633 tissue microarray (TMA) cores from 834 ccRCC patients. We defined a density-normalized Spatial Interaction Score was defined to quantify FOXP3+ regulatory T cell (Treg) enrichment within a 30 μm radius of CD8+ T cells. Survival analyses were performed using Kaplan-Meier curves with log-rank tests and multivariable Cox regression models. Results: PhenoSSP achieved a balanced accuracy of 71.0% and an F1-Macro of 70.7%, outperforming conventional methods. CD8+ T-cell density alone was not significantly associated with overall survival (OS, P = 0.057), whereas the Spatial Interaction Score was significantly associated with poor OS (log-rank test, P = 0.012) and was significantly higher in non-survivors (P = 0.032). Conclusion: This study reveals a spatial basis for immune evasion and poor prognosis in ccRCC: the pre-existing Treg enrichment near CD8+ T cells, rather than the abundance of effector cells, was associated with impaired antitumor immunity. The Spatial Interaction Score serves as a candidate prognostic biomarker and provides a rationale for Treg-targeting combination strategies in patients harboring spatially defined suppressive niches.
    Keywords:  Kidney cancer; deep learning; immune evasion; regulatory T cell; spatial biomarker; spatial proteomics; tumor microenvironment
    DOI:  https://doi.org/10.20517/cdr.2026.27
  32. Mod Pathol. 2026 Jun 09. pii: S0893-3952(26)00063-3. [Epub ahead of print] 101020
    Immune Related Pathological Features and Predictive Score in Intrahepatic Cholangiocarcinoma Treated With Combined Conversion Immunotherapy.
    Wanwan Chen, Yimeng Sang, Gwyneth Shook Ting Soon, Edwin Chew Jun Chen, Gaohua Wu, Xiyi Lin, Rongkui Luo, Qiang Gao, Jian Zhou, Hongping Xia, Kai Zhu, Ruoyu Shi.
      Immune checkpoint inhibitor (ICI)-based combined neoadjuvant/conversion therapy (NAT) is increasingly utilized in the management of initially unresectable intrahepatic cholangiocarcinoma (iCCA). Reliable biomarkers in predicting treatment and survival outcome remain underdeveloped. Here we assessed immune-related pathological features (irPF) in pre-treatment biopsy specimens of initially unresectable iCCA treated by ICI-based conversion therapy. A predictive scoring system (immune therapy predictive score, iTPS) was developed to predict the patients' oncological outcome. We evaluated 13 irPF (tumor infiltrating lymphocyte, mature tertiary lymphoid structure, lymphoid aggregate, dense plasma cell infiltration, granuloma, neutrophil, foamy macrophage, necrosis, cholesterol cleft, hemosiderin deposition, giant cell formation, neovascularization and mature fibrosis) in hematoxylin-eosin (HE) stained biopsy specimen slides from 95 iCCA patients. Cox regression analysis was used to evalutate the correlation between these features and recurrence-free survival (RFS) and overall survival (OS). Features showing correlation with survival were selected for iTPS to develop a binary iTPS scheme. Four features (immature fibrosis, tumor-infiltrating lymphocytes, lymphoid aggregate and hemosiderin) were included in iTPS. A binary iTPS scheme showed patients with low iTPS displaying significantly better RFS (hazard ratio [HR]: 1.83; 95% confidence interval [CI]: 1.02∼3.27, P = 0.04) and OS (HR: 12.9; CI: 3.07∼54.18, P < 0.001). In conclusion, we developed an iTPS scheme based on routine HE-stained pretreatment biopsy slides. The iTPS can predict the RFS and OS of iCCA patients treated by combined ICI-based conversion therapy. iTPS is a good candidate predictive biomarker in iCCA and provides a new perspective in understanding the tumor immune microenvironment in immunotherapy.
    Keywords:  Immune-related pathological features; Immunotherapy; Intrahepatic cholangiocarcinoma; Predictive marker
    DOI:  https://doi.org/10.1016/j.modpat.2026.101020
  33. Front Immunol. 2026 ;17 1817892
    AI-based pathomics model predicts regulatory T cell infiltration and radiotherapy response in IDH-wild-type glioblastoma.
    Shaoli Peng, Jialei Chen, Xuezhen Wang, Xingfu Wang, Qiuyuan Yue, Hailin Lan, Jingru Zhang, Yuqi Xie, Meiyan Yang, Jiayu Xiao, Chenyan Guo, Yang Wang, Zanyi Wu, Jinsheng Hong, Mingwei Zhang.
       Background: Regulatory T cells (Tregs) contribute significantly to immune suppression and therapy resistance in isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM), a highly aggressive brain tumor with poor prognosis.
    Methods: In this study, we developed an artificial intelligence (AI)-powered pathomics model to predict Treg infiltration and stratify prognosis in GBM patients undergoing radiotherapy. Using high-dimensional features extracted from hematoxylin and eosin-stained biopsies, we constructed a pathomics score (PS) via gradient boosting after feature selection with Minimum Redundancy Maximum Relevance (mRMR) and Relief algorithms.
    Results: The model demonstrated strong predictive performance across multi-center cohorts (n > 300), where high PS was significantly associated with elevated Treg levels and reduced overall survival (TCGA: HR = 2.16; validation cohort: HR = 1.706). Gene set enrichment analysis linked high PS to immune-evasive pathways, including Notch and IL-6/JAK/STAT3 signaling, along with increased expression of DNA repair gene RAD50, suggesting a potential association with radiotherapy response.
    Conclusion: This AI-based pathomics framework offers a robust and interpretable tool for immunoprofiling and outcome prediction, paving the way for precision radiotherapy and Treg-targeted therapeutic strategies in glioblastoma.
    Keywords:  artificial intelligence; glioblastoma; immunotherapy biomarkers; machine learning; pathomics; radiotherapy response; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1817892
  34. Melanoma Res. 2026 Jun 10.
    Meaningful efficacy measures and trial endpoints in patients with advanced melanoma being considered for adjuvant systemic therapy: a prospective patient survey study.
    Daniel Goldshtein, Yousuf Shad, Elaine McWhirter, Richard Tozer, Adi Kartolo.
      In this prospective, survey-based study conducted from May 2023 to February 2025 at the Juravinski Cancer Center, patient preferences and perceptions of clinically meaningful outcomes in the adjuvant treatment of resected stage IIB-IV melanoma were evaluated. Sixty-four eligible patients with resected stage IIB-IV melanoma who were considering adjuvant systemic therapy completed an online survey assessing their understanding and prioritization of treatment outcomes, thresholds for meaningful clinical benefit, and willingness to accept toxicity risks. Overall survival (OS) and quality of life (QoL) emerged as the most important endpoints, prioritized by 37 and 31% of respondents respectively, with patients choosing surveillance tending to prioritize QoL while those on active treatment favoured OS. Willingness to accept disease-free/progression-free benefit in the absence of an OS benefit declined as the risk of potential side effects increased, even among patients who ultimately chose active treatment. Patients considered a reduction in recurrence risk from 27 to 10% over 2 years (stage IIB-IIC) and from 50 to 20% over 5 years (stage III-IV) to be clinically meaningful, accepting a median 10-12.5% risk of significant side effects, and desired a minimum cancer-free interval of 4.75 years. These findings suggest that while OS remained a primary concern, many melanoma patients placed high value on QoL and were cautious about initiating adjuvant therapies without demonstrable survival benefit. Reluctance to accept hypothetical treatment with potential toxicity contrasted with those who proceeded with treatment. This highlighted the importance of incorporating patient preferences and risk tolerance into shared decision-making and trial design.
    Keywords:  adjuvants; immunologic; immunotherapy; melanoma; patient preference; patient-centered care
    DOI:  https://doi.org/10.1097/CMR.0000000000001114
  35. Eur J Cancer. 2026 Jun 05. pii: S0959-8049(26)00653-2. [Epub ahead of print]243 116872
    Progression risk among responders to PD-1/PD-L1 blockade is primarily stratified by response depth: A nationwide cohort study of 2127 patients with melanoma, RCC, and NSCLC.
    Rikke Andersen, Mette Syberg Jespersen, Mario Presti, Birgitte Bjornhart, Anne-Cathrine Østby, Anne Kirstine Moeller Darras, Yago Garitaonaindia, Christina Halgaard Ruhlmann, Malene Støchkel Frank, Henrik Schmidt, Rasmus Blechingberg Friis, Louise Mahncke Guldbrandt, Jon Røikjær Henriksen, Andreas Bjerrum, Kira Schreiner Simonsen, Jesper Andreas Palshof, Troels Holz Borch, Jon Lykkegaard Andersen, Soeren Kjaer, Niels Viggo Jensen, Aziza Azimi, Ane Bundsbaek Iversen, Peter Meldgaard, Sara Grønbech Steen, Shawez Khan, Adam Andrzej Luczak, Stine Wahlstrøm, Daniela Zitnjak, Inge Marie Svane, Niels Fristrup, Charlotte Kristiansen, Gitte Fredberg Persson, Lars Bastholt, Mette Poehl, Eva Ellebaek, Marco Donia.
       PURPOSE: Among responders to PD-1/PD-L1 blockade, it remains unclear whether tumour type and traditional baseline patient and tumour characteristics provide additional prognostic information for progression risk beyond response depth.
    METHODS: In this nationwide, population-based cohort study, we identified adults with metastatic melanoma (MM), renal cell carcinoma (RCC), or non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 monotherapy or dual checkpoint blockade. Analyses were restricted to responders by investigator-assessed RECIST (complete or partial response) with outcomes administratively censored at 5 years. Prespecified baseline and on-treatment variables were evaluated for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox models and assessed for consistency across tumour types.
    RESULTS: Among 2127 responders, PFS trajectories within response depth categories (complete response and partial response) were highly similar across MM, RCC, and NSCLC. Prespecified variables with prognostic value in the overall population, including performance status and treatment line, provided limited additional prognostic information once response depth was known. Depth of response (complete vs partial) was the strongest independent factor associated with progression risk within each tumour cohort.
    CONCLUSIONS: Among patients with MM, RCC, or NSCLC who achieved an objective response to PD-1/PD-L1 blockade, tumour type and traditional baseline prognostic factors provided limited additional stratification of progression risk once response depth was known. These findings suggest that, within the tumour types studied, response durability is primarily associated with response depth rather than other known clinical features, supporting prospective evaluation of response-guided follow-up strategies and interventions designed to deepen responses.
    Keywords:  Cohort study; Complete response; Immune checkpoint inhibitors; PD-1/PD-L1 blockade; Partial response; Progression-free survival
    DOI:  https://doi.org/10.1016/j.ejca.2026.116872
  36. Cancer Immunol Res. 2026 Jun 11.
    DNA hypomethylating agents preserve T cell stemness and potentiate the efficacy of CD3-bispecific antibodies.
    Mark Aleynick, Qingqing Wang, Jennifer E Wu, Samantha Lemus, Matthew Chaimowitz, Hannan Mir, Jacqueline J Warsaw, Chunguang Guo, Lynn E Macdonald, Janelle C Waite, Nikos Kourtis, Dimitris Skokos.
      Bispecific antibodies targeting tumor-associated antigens and CD3 are promising therapeutic agents for both solid and hematologic cancers. CD3-bispecifics induce T cell activation and cytotoxicity; however, prolonged TCR stimulation can lead to chromatin rewiring and T cell dysfunction, thereby limiting their full therapeutic potential. Here, we investigate the combination of CD3-bispecifics with the DNA hypomethylating agent decitabine and observe enhanced synergistic tumor growth inhibition in various preclinical models. Utilizing a PSMAxCD3 bispecific antibody for treatment of prostate carcinoma and in vivo humanized mouse disease models, we catalog, at the single-cell level, the dynamics of T cell epigenetic states during bispecific therapy and in combination with decitabine. Importantly, this combination strategy preserves a TCF-1+ T cell population and delays acquisition of a dysfunctional state at both chromatin and protein levels. At the DNA methylation level, TCR stimulation in the presence of decitabine maintains a naive-like pattern in gene loci associated with T cell stemness. This study provides a resource for understanding the evolution of T cell states during immunotherapy and mechanistic support for combining epigenetic modifiers with CD3-bispecifics in the clinic.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1420
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒14 at 5:06.