bims-tuinly 2026-05-31 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–05–31
thirty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Generation of functional canine TIL products for solid tumors.
S1P in Tumor Microenvironment and Modulation of Anti-Tumor-Directed T-Cell Responses.
Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Prognostic Significance, Predictive Value, and Emerging Directions for Clinical Implementation.
Immune Phenotyping Using Neutrophil-to-Lymphocyte Ratio and Tumor-Infiltrating Lymphocytes Predicts Recurrence in Resected Melanoma.
Early Recurrence of HCC Is Driven by Inflammation-Related HIF-1α Independent Angiogenesis Rather than Hypoxia-Induced Immune Escape.
Digital Pathology and the AI-Based Quantification of the Tumor Microenvironment in Gastrointestinal Cancer: From Tumor Budding and Tumor-Infiltrating Lymphocytes to Tertiary Lymphoid Structures.
Costimulatory biomarker-specific CD28 PET for early prediction of the response to PD-1 blockade in lung cancer.
Development and validation of an interpretable prediction model using spatial patterns of tumor-infiltrating lymphocytes in H&E-stained whole-slide images for immune subtyping of lung adenocarcinoma.
Leveraging CRISPR/Cas9 for optimized adoptive T cell therapies: From molecular engineering to clinical manufacturing.
The Differential Impact of Neoadjuvant Therapies on the Tumor Microenvironment, Peripheral Biomarkers, and Survival in Pancreatic Cancer: A Retrospective Cohort Study.
Nonoperative Management of Locally Advanced Resectable Cutaneous Squamous Cell Cancer of the Head and Neck with PD-1 Blockade.
Prognostic Impact of CD8+ and CD4+ Tumor-Infiltrating Lymphocytes and Perineural/Vascular Invasion in Laryngeal Squamous Cell Carcinoma.
Activation-dependent lentiviruses enable antigen-specific T cell expansion and transduction.
Spatiotemporal dynamics of adoptively transferred stem-like CD8 + T cells in the tumor microenvironment following vaccination.
PiggyBac-engineered membrane-bound IL-7 TILs combined with anti-PD-1 antibody demonstrates efficacy in recurrent ovarian cancer: a first-in-human phase 1 trial.
The immune landscape of melanoma microenvironmental crosstalk.
Molecular understanding and clinical aspects of adoptive cellular immunotherapy in prostate cancer.
Unlocking the potential: current landscape and future directions of immunotherapy in gastric cancer.
Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors.
A Retrospective Cohort Study Assessing the Prognostic Significance of Tumor-Associated Macrophages (TAMs) in Gastric Cancer in the Indian Population.
In vitro expansion of stem-like memory T cells via D-mannose supplementation.
ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.
Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.
Ripk2 promotes CD8+ T cell inactivation and hepatocellular carcinoma progression through Myb/Cxcl9 and Pax5/Adpgk signaling pathways.
Comparison of Stromal Tumor-Infiltrating Lymphocyte (sTIL) Levels and Clinicopathological Features in Neoadjuvant-Naive HER2-Low and HER2-Negative Primary Breast Cancers.
Reinvigorating the Cancer-Immunity Cycle by Intratumoral Administration of Conventional Dendritic Cells in Melanoma and Other Solid Tumors: A Narrative Review.
Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.
Immunoscore and beyond: evolution and clinical integration of immune contexture-based biomarkers across solid tumours.
PI3Kδ inhibition alters CD8 T cell differentiation and reprograms the tumor microenvironment following adoptive immunotherapy.
PD-1 regulates latent effector differentiation of thymic cytotoxic CD8+ T cells.
Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges.

Front Immunol. 2026 ;17 1810955

Generation of functional canine TIL products for solid tumors.

Kay M Foos, Veethika Pandey, Michael W Jennings, Daniel J Powell, Nicola J Mason.

  Immunotherapy based on the adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) has proven effective in treating human metastatic melanoma patients, but success in tumors with lower mutational burdens remains a challenge. Preclinical evaluation of cellular therapies commonly relies on murine models, which often require implantation of tumors into immunocompromised mice and thus do not accurately reflect the complex tumor-immune interactions seen in patients. Alternatively, spontaneous tumors in client-owned dogs serve as an underutilized and valuable parallel patient population for investigating the effectiveness of adoptive cell therapy in an immunocompetent host. However, TILs have been largely unexplored in dogs. Leveraging canine cancer patients with naturally occurring low tumor mutational burden (TMB) cancer types to study TIL therapy aims to enhance preclinical translatability. To evaluate the feasibility of TIL therapy in the veterinary sector, we developed protocols to reliably expand TILs from canine oral melanoma and appendicular osteosarcoma, despite low T cell frequencies in tumor digests. A subset of these TIL products showed reactivity to autologous tumor cells from fresh tumor digests as well as early passage cell lines. Lack of TIL reactivity in a beta-2-microglobulin (B2M)-ablated canine melanoma sample confirmed that recognition was major histocompatibility complex (MHC) class I-dependent. Together, these data establish the feasibility of generating functional canine TIL products and pave the way for comparative trials to evaluate TIL efficacy and novel strategies to enhance responses in low-TMB malignancies.

Keywords:  T cell activity; T cells; canine; cell killing; cytokines; interleukins; solid tumors; tumor infiltrating lymphocyte (TIL)

DOI:  https://doi.org/10.3389/fimmu.2026.1810955
Cells. 2026 May 15. pii: 909. [Epub ahead of print]15(10):

S1P in Tumor Microenvironment and Modulation of Anti-Tumor-Directed T-Cell Responses.

Patrícia A António, Joana R Lérias, Carolina M Gorgulho, Karina Balan, Vitaly Balan, Markus J Maeurer.

  Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8+ TILs exhibiting a progenitor stem-cell-like profile (CD39- CD69-). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the "double-edged sword" nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome.

Keywords:  CD69; S1P; T-cell receptor; sphingosine-1-phosphate receptor; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cells15100909
Cancers (Basel). 2026 May 13. pii: 1588. [Epub ahead of print]18(10):

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Prognostic Significance, Predictive Value, and Emerging Directions for Clinical Implementation.

Panuch Eiamprapaporn, Cindy Venegas Mata, Raj Nandani, Thiti Susiriwatananont, Keith L Knutson, Saranya Chumsri.

  Triple-negative breast cancer (TNBC) represents a biologically aggressive subtype with limited therapeutic targets; however, tumor-infiltrating lymphocytes (TILs) have emerged as the most robust immune biomarker with compelling prognostic and predictive significance. This comprehensive review synthesizes current evidence on TIL assessment methodology; the immunobiological landscape of TNBC, including regulatory T cell populations and PD-L1 correlations; gene expression underpinnings of the tumor immune microenvironment; and systematic evidence from meta-analyses and clinical trials. Meta-analytic estimates demonstrate that high TIL levels are associated with improved overall survival (HR 0.58, 95% CI 0.48-0.71) and disease-free survival (HR 0.66, 95% CI 0.57-0.76), with each 10% TIL increment conferring incremental benefit. High TILs predict superior pathologic complete response to neoadjuvant chemotherapy (OR 2.14, 95% CI 1.43-3.19), with lymphocyte-predominant breast cancer achieving pCR rates exceeding 80% with pembrolizumab-based chemoimmunotherapy. Future directions include prospective TIL-guided treatment trials, artificial intelligence-enabled standardization, and emerging adoptive TIL cellular therapies for metastatic disease.

Keywords:  PD-L1; adoptive cell therapy; biomarkers; immunotherapy; neoadjuvant therapy; pathologic complete response; triple-negative breast cancer; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18101588
Diagnostics (Basel). 2026 May 14. pii: 1495. [Epub ahead of print]16(10):

Immune Phenotyping Using Neutrophil-to-Lymphocyte Ratio and Tumor-Infiltrating Lymphocytes Predicts Recurrence in Resected Melanoma.

Omer Ekin, Oktay Halit Aktepe.

  Background and Objectives: Tumor-infiltrating lymphocytes (TIL) and the neutrophil-to-lymphocyte ratio (NLR) are each associated with prognosis in melanoma, yet their combined prognostic value remains insufficiently defined. We aimed to assess whether integrating NLR and TILs into a combined immune phenotype improves prediction of recurrence-free survival (RFS) in patients with resected cutaneous melanoma. Materials and Methods: A total of 203 patients were included. Receiver operating characteristic analysis identified an NLR cut-off of 2.75 for RFS, defining low (<2.75) and high (≥2.75) groups. TIL status was dichotomized as present or absent. According to the combined NLR-TIL profile, patients were initially categorized into three immune phenotypes: favorable (low NLR and TIL-positive), intermediate (low NLR and TIL-negative or high NLR and TIL-positive), and unfavorable (high NLR and TIL-negative). For the dichotomized analysis, the intermediate and unfavorable phenotypes were combined and compared with the favorable phenotype. Associations of clinicopathological factors with RFS were evaluated using Kaplan-Meier curves and Cox regression models. Results: The median follow-up was 56 months. In the univariate analysis, stage III disease, greater Breslow thickness, increased mitotic rate, and absence of adjuvant therapy were associated with worse RFS. In addition, patients with an unfavorable immune phenotype had a markedly increased risk of recurrence compared with those in the favorable group (HR 2.86, 95% CI 1.43-5.71; p = 0.004). In multivariate Cox regression analysis, both the unfavorable immune phenotype and stage III disease independently predicted RFS (HR 2.25, 95% CI 1.11-4.54; p = 0.024 and HR 2.13, 95% CI 1.03-4.43; p = 0.041, respectively). Conclusions: Combined assessment of systemic inflammation and tumor-local immune response using NLR and TILs may provide meaningful prognostic stratification in resected cutaneous melanoma.

Keywords:  cutaneous melanoma; neutrophil-to-lymphocyte ratio; prognosis; recurrence-free survival; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.3390/diagnostics16101495
Biomolecules. 2026 May 14. pii: 723. [Epub ahead of print]16(5):

Early Recurrence of HCC Is Driven by Inflammation-Related HIF-1α Independent Angiogenesis Rather than Hypoxia-Induced Immune Escape.

Lianda Siregar, Rino Alvani Gani, Toar J M Lalisang, Irsan Hasan, Suhendro, Heriawan Soejono, Siti Boedina Kresno, Nurjati Chairani Siregar, Muhammad Begawan Bestari.

   BACKGROUND: Hepatocellular carcinoma (HCC) shows a high rate of early recurrence after curative resection, indicating a critical contribution of tumor microenvironment-driven molecular mechanisms. Early recurrence of hepatocellular carcinoma is defined as recurrence within 6 months after curative resection, with a prevalence exceeding 30%. Hypoxia signaling and immune dysregulation have been implicated, yet their compartment-specific relevance remains unclear.
METHODS: This multicenter nested case-control study included 49 HCC patients to evaluate associations between hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), tumor-infiltrating lymphocytes (TILs), CD4+ T cells, CD8+ T cells, regulatory T cells (Tregs), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1) and early recurrence after resection. TIL density was assessed using hematoxylin and eosin staining, while immunohistochemistry was performed to quantify intratumoral and peritumoral expression of the studied markers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive performance. Recurrence-free survival (RFS) was analyzed using the Kaplan-Meier, and independent predictors were identified using multivariate Cox proportional hazards regression.
RESULTS: Early recurrence occurred in 11 of 49 patients (22.4%) of Child-Pugh A patients. Recurrent tumors were characterized by elevated VEGF expression despite absent HIF-1α, alongside significant depletion of intratumoral TILs (HR 5.02; 95% CI 1.09-23.26), CD4+ (HR 7.68; 95% CI 1.66-35.60) and CD8+ cells (HR 6.68; 95% CI 1.77-25.23) and reduced peritumoral CD8+ infiltration (HR 4.20; 95% CI 1.11-15.91). Multivariable analysis identified low intratumoral CD4+ (HR 7.98; 95% CI 1.63-39.07) and reduced peritumoral CD8+ expression (HR 4.98; 95% CI 1.14-21.70) as independent predictors, whereas HIF-1α, VEGF, Treg, PD-1, and PD-L1 were not significantly associated.
CONCLUSIONS: Early HCC recurrence shows HIF-1α-independent angiogenesis alongside spatial immune depletion, supporting integrated immune profiling over single angiogenic markers.

Keywords:  CD4; CD8; PD-1; PDL1; T regulation; VEGF; angiogenesis; early recurrence; hepatocellular carcinoma; hypoxia

DOI:  https://doi.org/10.3390/biom16050723
Int J Mol Sci. 2026 May 14. pii: 4386. [Epub ahead of print]27(10):

Digital Pathology and the AI-Based Quantification of the Tumor Microenvironment in Gastrointestinal Cancer: From Tumor Budding and Tumor-Infiltrating Lymphocytes to Tertiary Lymphoid Structures.

Justyna Łapińska, Klaudia Kasperczuk, Klaudia Kańczugowska, Aleksandra Gałan, Weronika Pająk, Jakub Kleinrok, Ryszard Sitarz, Jacek Baj, Agnieszka Korolczuk.

  Advances in digital pathology and artificial intelligence (AI) are significantly transforming the approach to analyzing the tumor microenvironment (TME) in gastrointestinal cancers (GICs). The TME consists of tumor cells, stromal components, and immune cells. It plays a key role in disease progression, treatment response, and patient prognosis. This review discusses the most important TME biomarkers, such as tumor budding (TB), tumor-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLSs), with emphasis on their prognostic and predictive significance. Traditional histopathological assessment of these parameters is limited by subjectivity, intraobserver variability, and time-consuming nature. In this context, AI-based tools enable automated, quantitative, and more reproducible analysis of entire histological sections. Deep learning models allow the accurate detection and classification of structures and also analysis of their spatial organization. They provide new biological insights unavailable in routine diagnostics. The integration of imaging data with molecular and clinical information leads to the development of personalized medicine. Despite numerous advantages, the implementation of AI in clinical practice continues to face challenges related to standardization, data availability, and model interpretability.

Keywords:  artificial intelligence; digital pathology; gastrointestinal cancers; tertiary lymphoid structures; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/ijms27104386
Mol Ther. 2026 May 27. pii: S1525-0016(26)00398-9. [Epub ahead of print]

Costimulatory biomarker-specific CD28 PET for early prediction of the response to PD-1 blockade in lung cancer.

Yang Yang, Jiannan Wang, Hong Yu, Zhen Quan, Zhujiao Zhang, Jingran Guo, Haoxuan Wu, Shanshan Liu, Xiaoqian Li, Xinxin Hu, Hongyan Zou, Mengyuan Zhu, Tianyi Wang, Zijian Zhou, Jiaying Liu, Jing Wang, Kai Wang, Lili Yang, Zhaoguo Han, Xilin Sun.

The costimulatory receptor CD28 is indispensable for regulating T-cell effector function, and the absence of co-stimulation is associated with poor immunotherapy response. However, longitudinal molecular imaging studies targeting CD28 as a costimulatory biomarker using positron emission tomography (PET) have not been reported. Here, we developed the co-stimulation-associated radiotracer [89Zr]Zr-DFO-anti-CD28 to enable early prediction of therapeutic response by identifying recovery of T-cell responsiveness following programmed cell death protein 1 (PD-1) blockade in lung cancer. [89Zr]Zr-DFO-anti-CD28 demonstrated high specificity for CD28+ tumor-infiltrating lymphocytes (TILs) in vitro and in vivo. By monitoring CD28 expression and its loss within the tumor microenvironment, [89Zr]Zr-DFO-anti-CD28 PET identified responses to anti-PD-1 therapy earlier than changes in tumor volume observed at day 5, and increased radiotracer uptake correlated with more favorable treatment responses. Repeated PET imaging was performed to monitor dynamic changes in CD28+ TILs induced by different immunotherapies at day 14, and [89Zr]Zr-DFO-anti-CD28 PET captured the CD28-dependent restoration of T-cell effector function, further supporting its potential for early prediction. Taken together, costimulatory biomarker-specific CD28 PET molecular imaging may enable noninvasive early prediction of responses to multiple immunotherapies and facilitate the application of precision medicine in lung cancer.

DOI: https://doi.org/10.1016/j.ymthe.2026.05.011
Front Immunol. 2026 ;17 1773927

Development and validation of an interpretable prediction model using spatial patterns of tumor-infiltrating lymphocytes in H&E-stained whole-slide images for immune subtyping of lung adenocarcinoma.

Xia Li, Hai-Zhen Qin, Jing-Yu Wei, Kang-Lai Wei, Zhao-Quan Huang.

   Objective: To develop an interpretable prediction model for lung adenocarcinoma immune subtyping by quantifying spatial distribution patterns of tumor-infiltrating lymphocytes in H&E whole-slide images, providing a computational tool for tumor immune microenvironment evaluation.
Methods: Immune subtyping was performed on the TCGA lung adenocarcinoma cohort using ssGSEA to quantify immune gene set activity, followed by hierarchical clustering and t-SNE visualization to stratify patients into high- and low-immunity subgroups. Immune cell infiltration was assessed using CIBERSORT, while tumor mutation burden and somatic mutation profiles were analyzed with maftools. Differential expression and functional enrichment analyses were conducted using GO and KEGG databases. In pathological image analysis, an automated annotation model optimized with study-specific data was employed to process whole-slide images. Immune subtype prediction criteria were established by quantifying spatial distribution features of tumor-infiltrating lymphocytes. The model's predictive performance was validated in both internal and external cohorts.
Results: Transcriptomic analysis stratified 503 LUAD patients into high- and low-immunity subgroups. The high-immunity group exhibited elevated infiltration of CD8+T cells and M1 macrophages, higher tumor mutation burden, and enriched T cell activation pathways. The low-immunity group showed predominant resting immune cells. The automated annotation model, achieved a 95.09% Dice score for tissue contour segmentation, 91.53% for tumor parenchyma segmentation, and a 79.51% F1-score with an mAP@0.5 of 82.13% for TIL identification. Quantitative TIL spatial distribution analysis with a 0.2 high-attention threshold enabled development of an immune subtyping model using a 0.05 classification cutoff, which achieved an AUC of 0.839 for immune subtype classification in the internal validation cohort. In the external validation cohort, the model achieved an AUC of 0.927, and immunohistochemical analysis confirmed significantly higher densities of CD3+, CD8+, CD20+, and CD68+ cells in predicted high-immunity samples.
Conclusion: This study establishes an interpretable immune subtype prediction model for LUAD based on TIL spatial distribution in H&E-stained sections. Through a modular design that integrates deep learning-based annotation with statistical classification, the model links morphological phenotypes to molecular immune subtypes while maintaining transparency and verifiability throughout the analytical workflow. This cost-effective and scalable tool offers potential value for assessing tumor immune status and guiding immunotherapy decision-making.

Keywords:  computational pathology; immune subtyping; interpretable model; lung adenocarcinoma; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1773927
Biochem Biophys Res Commun. 2026 May 20. pii: S0006-291X(26)00767-9. [Epub ahead of print]826 154003

Leveraging CRISPR/Cas9 for optimized adoptive T cell therapies: From molecular engineering to clinical manufacturing.

Ji-Hyeon Kim, Hyo Jung Cho, Hyang-Mi Lee.

  Cancer immunotherapy is rapidly evolving from pharmacologic immune modulation to adoptive cell therapy (ACT). In ACT, T cells are expanded and genetically engineered ex vivo to achieve long-lasting antitumor activity. The primary ACT platforms-tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR) T cells, and T-cell receptor (TCR) T cells-rely on T-cell effector function but differ in their mechanisms of antigen recognition, HLA dependence, and engineering requirements, leading to unique clinical strengths and limitations. CRISPR/Cas9 genome editing provides precise knock-out (KO) and knock-in (KI) strategies, allowing for multiplex editing and functional modulation across the genome. In the context of ACT manufacturing, CRISPR/Cas9 addresses critical challenges such as T-cell exhaustion, graft-versus-host disease (GvHD), and ensuring product consistency and quality. This article explores how CRISPR/Cas9 can be utilized to overcome the limitations of ACT and summarizes the current clinical landscape of CRISPR-engineered ACT products. Finally, we discuss the ongoing challenges associated with CRISPR-based genome editing and propose potential solutions.

Keywords:  Adoptive T cell therapy; CAR-T; CRISPR/Cas9; Multiplex gene editing; TCR-T; TIL

DOI:  https://doi.org/10.1016/j.bbrc.2026.154003
Cancers (Basel). 2026 May 12. pii: 1567. [Epub ahead of print]18(10):

The Differential Impact of Neoadjuvant Therapies on the Tumor Microenvironment, Peripheral Biomarkers, and Survival in Pancreatic Cancer: A Retrospective Cohort Study.

Trevor Silva, Tomoko Yamazaki, John M Creasy, Jon M Gerry, Binbin Zheng-Lin, Amar J Srivastava, Kristina H Young.

  Background/Objectives: The selection of neoadjuvant therapy for patients with non-metastatic pancreatic adenocarcinoma remains challenging. Methods: We performed a single-institution, retrospective analysis of 79 patients who underwent resection of their pancreatic adenocarcinoma after receiving neoadjuvant therapy. Clinical and pathologic data were collected. Tumor fibrosis was quantified using Masson's trichrome staining, tumor-infiltrating lymphocytes (TIL) were evaluated by an AI-based analysis of whole-slide H&E images, and immune cell populations were quantified by multiplex immunohistochemistry. Correlation analyses were performed between neoadjuvant treatment regimen, tumor regression, immune phenotypes, and survival. Results: All patients received chemotherapy, 77% FOLFIRINOX and 23% Gemcitabine/nab-paclitaxel (Abraxane). Eighteen percent of patients went on to receive radiation. Tumor regression grade (TRG) correlated with the neoadjuvant regimen. A reduction in tumor markers and the baseline neutrophil-to-lymphocyte ratio (NLR) correlated with overall survival. Among patients with an NLR > 3.3, FOLFIRINOX conferred a survival benefit over Gemcitabine/nab-paclitaxel, and radiation trended towards improved survival. Radiation was associated with increased fibrosis and reduced infiltration of CD8+ and regulatory T cells (Tregs). Increased Tregs and PDL1+ stromal cells were associated with poor response to neoadjuvant therapy, and NLR > 3.3 correlated with increased Treg infiltration. Conclusions: Our data suggest that patients with a high baseline NLR may benefit from intensified neoadjuvant therapy with FOLFIRINOX and radiation. Combination immunotherapy targeting Tregs and the PD1/PDL1 axis may further improve outcomes.

Keywords:  neoadjuvant therapy; neutrophil-to-lymphocyte ratio; pancreatic cancer; radiation; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers18101567
Clin Cancer Res. 2026 May 29.

Nonoperative Management of Locally Advanced Resectable Cutaneous Squamous Cell Cancer of the Head and Neck with PD-1 Blockade.

Fergal G Kavanagh, Ryan S Instrum, Lillian A Boe, Alana J Eagan, Daniel W Scholfield, Emma A Finnegan, Richard J Wong, Luc G Morris, Thomas J Ow, Winston Wong, Christopher A Barker, Nadeem Riaz, Melissa P Pulitzer, Klaus J Busam, Snehal G Patel, James Fetten, Ian Ganly.

PURPOSE: Neoadjuvant PD-1 blockade has shown marked efficacy before surgery in patients with head and neck cutaneous squamous cell cancer (CSCC). However, the potential for PD-1 blockade as a definitive, non-operative therapy remains uncertain.
PATIENTS AND METHODS: We conducted a single-institution retrospective study(2018-2023)of patients with locally advanced resectable stage III/IV CSCC treated with cemiplimab. Patients received neoadjuvant cemiplimab followed by surgery or cemiplimab monotherapy without surgery. The primary endpoint was objective radiological (assessed using iRECIST)and clinical response rate; secondary endpoints included disease-specific survival (DSS),progression-free probability(PFP),histopathologic response, and exploratory genomic biomarkers.
RESULTS: Fifty-one patients received cemiplimab monotherapy alone (median age;78.8 years) and 21 received neoadjuvant cemiplimab followed by surgery (median age;73 years). The 2-year DSS and PFP for cemiplimab monotherapy were 90% (95% CI, 80-100%) and 82% (95% CI, 72-94%), respectively. The 2-year DSS and PFP for neoadjuvant cemiplimab with surgery were 95% (95% CI, 86-100%) and 78% (95% CI, 62-100%), respectively. Tumor-infiltrating lymphocytes (TILs) were higher in patients with complete or partial response than in patients with progressive or stable disease (p=0.005, q=0.026), with absent TILs more frequent in non-responders. Tumor mutational burden was greater in complete (55.7) and partial (14.9) response than in progressive disease (4.9; p=0.02, q=0.04).
CONCLUSIONS: n this retrospective, non-randomized cohort, definitive-intent cemiplimab monotherapy was associated with durable disease control in selected patients with locally advanced resectable head and neck CSCC. This study provides a promising real-world organ preservation experience for patients with advanced head and neck CSCC treated with cemiplimab monotherapy that does not compromise oncologic outcomes.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0123
Iran J Pathol. 2026 ;21(2): 240-251

Prognostic Impact of CD8+ and CD4+ Tumor-Infiltrating Lymphocytes and Perineural/Vascular Invasion in Laryngeal Squamous Cell Carcinoma.

Maryam Lotfi, Mina Majdi, Parin Tanzifi, Tahereh Yousefi, Elham Nazar, Aysan Nozheh.

   Background & Objective: Squamous cell carcinoma (SCC) is characterized by infiltration of CD4+ and CD8+ T lymphocytes, which represent an early host immune response against malignant cells. This immune response may inhibit tumor progression and suppress malignancy. This study aimed to evaluate the density of CD4+ and CD8+ lymphocytes and their ratio within tumor nests and surrounding stroma in conventional laryngeal SCC. It also examined associations with prognostic factors such as regional lymph node metastasis, tumor histologic differentiation, vascular invasion, and perineural invasion.
Methods: This retrospective study analyzed 54 laryngeal SCC samples from patients who underwent total laryngectomy and cervical lymph node dissection without prior neoadjuvant chemoradiation therapy. Immunohistochemistry was used to assess CD4+ and CD8+ T lymphocytes in tumor nests and surrounding stroma. Statistical analyses evaluated correlations between lymphocyte infiltration and prognostic factors, including lymph node metastasis, histologic differentiation, vascular invasion, and perineural invasion.
Results: A significant association was found between high intratumoral CD8+ T lymphocyte density and a lower incidence of vascular and perineural invasion (mean, 10.9 cells/HPF vs 4.5 cells/HPF; p = 0.03). No significant correlations were observed between lymphocyte density and lymph node metastasis or tumor histologic differentiation.
Conclusion: High intratumoral CD8+ T-cell infiltration correlates with reduced vascular and perineural invasion in laryngeal SCC, suggesting a protective role in limiting tumor invasiveness. These findings highlight the prognostic significance of CD8+ T lymphocytes and warrant further research into immune mechanisms affecting SCC progression and patient outcomes.

Keywords:  CD4+; CD8+; Laryngeal squamous cell carcinoma; T lymphocytes; histologic grading; lymph node metastasis

DOI:  https://doi.org/10.22034/ijp.2026.2066899.3493
bioRxiv. 2026 May 13. pii: 2026.05.11.724165. [Epub ahead of print]

Activation-dependent lentiviruses enable antigen-specific T cell expansion and transduction.

Blake E Smith, Lindsey M Draper, Andrea Garmilla, Caleb R Perez, Nishant Singh, Lucia T Padilla, Ellen J K Xu, Stephanie A Gaglione, Jiao Shen, Winiffer D Conce Alberto, Qingyang Henry Zhao, Connor S Dobson, Kole T Roybal, Michael Dougan, Michael E Birnbaum, Stephanie K Dougan.

Cancer immunotherapies rely on tumor-specific T cells, which arise endogenously in most patients with cancer, but can be low frequency and poorly functional. Methods to specifically identify, expand, and manipulate tumor-specific T cells at the rare frequencies found in peripheral blood would enable new immunotherapeutic strategies. Here, we demonstrate an approach to virally transduce polyclonal tumor-reactive T cells across any MHC haplotype and in the absence of knowing the cognate antigen. By generating lentiviral vectors that selectively transduce cells expressing 4-1BB (CD137), a marker of T cell activation, we can transduce antigen-specific T cells with user-defined genetic cargoes that can selectively expand and track individual clonotypes via single-cell sequencing. Anti-4-1BB lentiviruses (4-1BB LVs) encoding therapeutic cargoes can also enhance antigen-specific T cells to extend survival in a xenograft model of human melanoma and transduce tumor-infiltrating T cells from patients with ovarian cancer. Overall, the 4-1BB LV platform targets antigen-specific T cells in a manner agnostic to both the antigen and presenting MHC, with potential applications in adoptive cell therapy manufacturing and TCR identification.
One Sentence Summary: Engineered lentiviral vectors targeting 4-1BB selectively activate, expand, and transduce antigen-specific T cells with immunomodulatory cargo.

DOI: https://doi.org/10.64898/2026.05.11.724165
bioRxiv. 2026 May 14. pii: 2026.05.12.724323. [Epub ahead of print]

Spatiotemporal dynamics of adoptively transferred stem-like CD8 + T cells in the tumor microenvironment following vaccination.

Dalton Hermans, Sloane C Fussell, Andrei Ramirez-Valdez, Sam Shepard, Remi Poulard, Sonia Zumalave, Benjamin Sievers, Christopher M Garliss, Vincent L Coble, Geoffrey M Lynn, Andrew S Ishizuka, Isidro Cortes-Ciriano, Robert A Seder.

Adoptive cell therapy (ACT) of tumor-specific T cells can improve survival in a subset of cancer patients. Current ACT approaches may be limited by using highly differentiated T cells which can be inhibited by an immunosuppressive tumor microenvironment (TME). Here, we developed an approach to optimize ACT and used spatial transcriptomics to show how stem-like and effector CD8 + T cells differentially mediate tumor control following vaccination. Spatial transcriptomic profiling of the TME showed that ACT with stem-like T cells followed by intravenous vaccination prevented immune exclusion, increased infiltration of pro-inflammatory macrophages, and reprogrammed tumor cells to upregulate Type I and Type II IFN signaling and apoptotic gene programs. The protective transcriptomic signature of the TME in this ACT model contained overlapping biomarkers with patients who responded to ACT therapy. This approach demonstrates synergy between transferred stem-like T cells and intravenous vaccination to transcriptionally remodel the TME and enhance tumor control.

DOI: https://doi.org/10.64898/2026.05.12.724323
Clin Cancer Res. 2026 May 26.

PiggyBac-engineered membrane-bound IL-7 TILs combined with anti-PD-1 antibody demonstrates efficacy in recurrent ovarian cancer: a first-in-human phase 1 trial.

Jing Guo, Yuliang Wu, Wei Huang, Guihai Ai, Chunyan Wang, Ning Luo, Jihui Zhu, Yang Zhou, Weihui Shi, Jingye Ding, Yao Ge, Weiwei Feng, Huajun Jin, Binghui Zhao, Zhongping Cheng.

PURPOSE: Recurrent ovarian cancer (rOC) remains an unmet need. This first-in-human phase 1 trial evaluated GC203, an autologous tumor-infiltrating lymphocyte (TIL) product genetically modified via piggyBac transposon to overcome the immunosuppressive tumor microenvironment (TME).
PATIENTS AND METHODS: A cohort of 18 patients with rOC who were heavily pretreated (median, 3.5 prior lines of therapy) underwent lymphodepletion with cyclophosphamide and hydroxychloroquine, followed by GC203 infusion. The primary endpoints were safety and tolerability. Secondary endpoints, assessed in the full analysis set (FAS) using RECIST 1.1 guidelines, encompassed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses included the Morisita Overlap Index (MOI) to quantify T cell receptor (TCR) repertoire similarity between infused TILs and circulating T cells.
RESULTS: The GC203 regimen demonstrated a favorable safety profile. Treatment-related adverse events were primarily hematological, with grade≥3 lymphopenia and neutropenia each occurring in 57% of patients. All proved to be transient with a median resolution 7 days. The regimen achieved an unconfirmed ORR of 33.3% (6/18 patients) alongside a disease control rate (DCR) of 83.3%. Survival analyses revealed a median PFS of 7.2 months (95% CI: 1.0-13.4) and a median OS of 17.1 months (95% CI: 9.5-24.7). A key exploratory analysis identified the MOI as a significant predictor of treatment response, achieving an area under the curve (AUC) of 0.79.
CONCLUSION: The GC203 regimen, combining piggyBac-mbIL-7 autologous TILs with anti-PD-1 antibody, demonstrates favorable safety and promising efficacy in heavily pretreated rOC, which supports its further development in this high-need population.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4130
Front Immunol. 2026 ;17 1847963

The immune landscape of melanoma microenvironmental crosstalk.

Qianqian Yang, Qingjing Yang, Bolin Xu, Xingyu Chen, Huilan Zheng, Mingming Wang, Winjin Zhang, Jingping Wu, Hongbin Cheng.

  Melanoma is a highly aggressive skin malignancy characterized by early metastasis, marked therapeutic resistance, and poor clinical outcomes in advanced disease. Increasing evidence indicates that immune dysregulation within the tumor microenvironment (TME) is a central determinant of melanoma progression, metastatic dissemination, and treatment failure. The melanoma immune microenvironment is shaped by complex interactions among tumor-associated macrophages, tumor-infiltrating lymphocytes, regulatory T cells, myeloid-derived suppressor cells, stromal cells, endothelial cells, and extracellular matrix components, together with hypoxia and acidosis, all of which cooperatively drive immune evasion, chronic inflammation, angiogenesis, and resistance to therapy. Mechanistically, cancer-associated fibroblasts promote immune tolerance by secreting CXCL12 and CCL17, thereby recruiting regulatory T cells and reinforcing a suppressive stromal niche; melanoma-derived factors and metabolic perturbations reprogram tumor-associated macrophages toward a pro-tumoral phenotype through lipid metabolic remodeling, endoplasmic reticulum stress, and immunosuppressive mediator production; and hypoxic stress amplifies CD39/CD73-dependent adenosine generation, which suppresses dendritic cell maturation and cytotoxic T-cell activity while facilitating immune escape. These immunosuppressive networks not only impair effective antitumor immune surveillance but also limit the long-term efficacy of immune checkpoint blockade and other systemic treatments. This review summarizes the immunopathological mechanisms underlying melanoma progression within the immune microenvironment and highlights emerging therapeutic strategies targeting immune and stromal crosstalk, providing a valuable theoretical basis for understanding melanoma immune escape and an important reference for the development of more effective and durable immunotherapeutic interventions.

Keywords:  cancer-associated fibroblasts; extracellular matrix; immune cells; immunotherapy; melanoma; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1847963
Crit Rev Oncol Hematol. 2026 May 27. pii: S1040-8428(26)00282-9. [Epub ahead of print] 105395

Molecular understanding and clinical aspects of adoptive cellular immunotherapy in prostate cancer.

Xinhong Du, Zhenhong Yan, Peng Su, Hongyuan Liang, Dan Dong, Kefeng Wang.

  Adoptive cellular immunotherapy (ACT) is a milestone therapeutic strategy that directly eliminates tumor cells or enhances anti-tumor immunity through the infusion of activated and expanded autologous lymphocytes in vitro. ACT has shown great potential as a treatment strategy for diverse malignant hematopoietic tumors. However, in solid tumors, this success has not been replicated due to the immunosuppressive mechanism within the tumor microenvironment (TME), low tumor antigenicity, infiltration of suppressive immune cells, and the emergence of severe adverse events (AEs). In recent years, chimeric antigen receptor T cells (CAR-T), T-cell receptor-engineered T cells (TCR-T), chimeric antigen receptor natural killer cells (CAR-NK), bispecific T-cell engagers (BiTEs), and CAR-macrophages (CAR-M) have been extensively investigated, and are expected to offer improved safety, feasibility and therapeutic efficacy in solid tumors. Prostate cancer (PCa) is initially androgen dependent. However, once the disease progresses to metastatic castration-resistant PCa (mCRPC) and drug resistance occurs, current treatments often fail to achieve satisfactory outcomes. As an immunotherapeutic approach, ACT offers a novel therapeutic concept for the treatment of mCRPC. This review presents a comprehensive overview of the development and mechanisms of various ACT strategies, with the aim of providing a theoretical and experimental basis for future therapeutic development.

Keywords:  Adoptive cellular immunotherapy; BiTE; CAR-M; CAR-NK; CAR-T; Prostate cancer; TCR-T

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105395
Front Immunol. 2026 ;17 1742723

Unlocking the potential: current landscape and future directions of immunotherapy in gastric cancer.

Yingfei Zhou, Luling Wei, Luoyang Wang, Bei Zhang, Jie Liang.

  Gastric cancer (GC) ranks as the third leading cause of cancer-related mortality worldwide, and its management remains formidable. Immunotherapy has been highly praised for its remarkable efficacy and acceptable toxicity, and its development has outpaced that of traditional therapies. However, molecular heterogeneity and the immunosuppressive tumor immune microenvironment (TIME) have hindered the treatment response of a considerable number of patients. This review synthesizes the latest therapeutic advances, spanning immune-checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), monoclonal antibodies and antibody drug conjugates (ADCs), cancer vaccines, tumor-infiltrating lymphocyte (TIL) therapy, and CAR-T cells therapy. Emerging strategies such as RNA interference nano-delivery systems, immune adjuvants, and microbiota modulation are constantly evolving to transform "cold" tumors into "hot" tumors. Persistent challenges include primary resistance, immune-related adverse events (irAEs) and antigenic heterogeneity, underscoring the imperative for refined patient stratification. Classical biomarkers such as PD-L1 expression, tumor mutational burden (TMB), mismatch-repair status, Epstein-Barr virus (EBV) positivity and circulating tumor DNA (ctDNA) all demonstrate predictive value but remain constrained by spatial heterogeneity and temporal dynamics. Consequently, we highlight emerging biomarkers that integrate metabolic, epigenetic and cell-death signatures, providing a roadmap for precision immunotherapy and continuous optimization of GC treatment algorithms.

Keywords:  biomarker; clinical trial; gastric cancer; immunotherapy; molecular target

DOI:  https://doi.org/10.3389/fimmu.2026.1742723
Ann Oncol. 2026 May 22. pii: S0923-7534(26)00880-X. [Epub ahead of print]

Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors.

Ecaterina E Dumbrava, Daniel Olson, Mohamed A Gouda, Mridula A George, Samuel D Saibil, Maria Apostolopoulou, Michael Bishop, Miriam N Gavriliuc, Amber M Kennon, Jordan A Weiss, Chris Ayers, Kara Moss, Christopher W Helsen, Donna Rill, Andreas G Bader, Deyaa Adib, Benjamin L Schlechter.

  The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 106 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.

Keywords:  Autologous T Cell Therapy; HER2; T Cell Antigen Coupler; TAC01-HER2

DOI:  https://doi.org/10.1016/j.annonc.2026.05.696
Iran J Pathol. 2026 ;21(2): 223-231

A Retrospective Cohort Study Assessing the Prognostic Significance of Tumor-Associated Macrophages (TAMs) in Gastric Cancer in the Indian Population.

Muskaan Arora, Saraswathy Sreeram, Adarsh Sugathan, Hema Kini, Pooja K Suresh, Jyoti R Kini.

   Background & Objective: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment and may hold prognostic significance in gastric cancer (GC). Limited data are available from the Indian population.
Methods: In this retrospective study, CD68 immunohistochemistry was performed on 60 surgically resected gastric adenocarcinomas. TAM density was quantified as the average number of positive cells per high-power field and categorised into low and high groups using a cutoff of 50 cells/HPF. Associations with clinicopathological features were analysed using chi-square and logistic regression.
Results: High TAM density was observed in 70% of cases and was significantly associated with larger tumor size (p = 0.05), increased tumor-infiltrating lymphocytes (p = 0.021), advanced pT stage (p = 0.007), lymph node metastasis (p < 0.001), and advanced clinical stage (p = 0.009). On multivariate analysis, lymph node metastasis remained an independent predictor of high TAM density (adjusted OR = 2.5; 95% CI: 1.02-6.2; p = 0.04).
Conclusion: CD68+ TAM density correlates with adverse pathological features in GC and may serve as a useful prognostic marker for patient risk stratification.

Keywords:  Immunotherapy; India; Prognosis; Stomach Neoplasms; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.22034/ijp.2026.2065021.3486
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00093-2. [Epub ahead of print]207 107-118

In vitro expansion of stem-like memory T cells via D-mannose supplementation.

Yajing Qiu, Congcong Zhao, Guideng Li, Bo Huang.

  The therapeutic success of adoptive T cell therapy (ACT) is closely tied to the in vivo persistence and differentiation state of transferred T cells. Clinical evidence consistently shows that less differentiated T cells, particularly memory T cells with stem-like properties, offer superior antitumor activity and long-lasting immune responses. However, these stem-like memory T cells are challenging to expand efficiently using conventional in vitro culture protocols. Existing strategies, such as brief CD3/CD28 antibodies co-stimulation combined with cytokines like IL-7, IL-15, and IL-21, have shown limited success but remain costly and operationally complex, hindering scalability for clinical use. There is a critical need for a rapid, efficient, cost-effective, and clinically viable method to induce and expand this T cell subset. Here, we present an optimized mannose-based culture approach that enables robust in vitro expansion of stem-like memory T cells, offering a practical solution to current limitations and paving the way for improved ACT applications.

Keywords:  Metabolic regulation; T cell differentiation; adoptive T cell therapy; anti-tumor immunity; stem-like memory T cells

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.025
PLoS Genet. 2026 May 26. 22(5): e1012107

ZBP1 Drives CD8+ T cell-mediated anti-tumor immunity in head and neck squamous cell carcinoma.

Yu Min, Ge Song, Lianlian Yang, Ling He, Shihong Xu, Kun Gao, Zheran Liu, Xingchen Peng, Lei Dai.

Head and neck squamous cell carcinoma (HNSCC) frequently resists PD-1 blockade due to an immunologically "cold" tumor microenvironment (TME). Here, we identify Z-DNA binding protein 1 (ZBP1) as a key immunoregulator that reprograms immune-suppressive TMEs. Integrated TCGA/SangerBox analyses revealed ZBP1 as a hub gene strongly correlated with cytotoxic CD8+ T cells (r = 0.48, p < 0.0001) and M1 macrophages (r = 0.39, p < 0.0001). Multi-model validation in 92 HNSCC specimens revealed elevated ZBP1 expression versus normal tissues (p < 0.01), co-localized with infiltrating CD8+/CD4+ T cells and CD68+ macrophages through multiplex immunofluorescence. Clinically, high ZBP1 predicted improved survival (HR = 0.61 for overall survival; HR = 0.45 for disease specific survival; p < 0.0001) and early-stage presentation (p = 0.004). Mechanistically, ZBP1 overexpression in SCC-7/MOC2 models suppressed tumor growth while enhancing IFN-γ+ CD8+ T cell activation and reducing M2 polarization (CD206+: 16.91% vs 38.19% in ZBP1-high vs control, p < 0.001). Single-cell transcriptomics uncovered ZBP1-driven TME remodeling through chemokine signaling networks and expanded effector T cell compartments, validated by 1.49-fold increased CD8+ T cell infiltration via flow cytometry. Spatial analysis revealed ZBP1 overexpression amplified immune cell crosstalk (1.65-fold interaction increase, p < 0.001), upregulating CD8+ T cell chemotaxis (CXCR3/CCR5-CCL5 axis) and effector functions (p < 0.0001). Concurrently, it suppressed immunosuppressive pathways (ARG1 ↓ /IDO1↓) through metabolic reprogramming, establishing ZBP1 as a dual regulator synchronizing lymphocyte recruitment and myeloid suppression. Our integrative approach bridges computational biology with functional validation, demonstrating ZBP1's capacity to convert "cold" tumors into immunologically active niches. This work positions ZBP1 as both a stratification biomarker for checkpoint inhibitor response and a therapeutic target for TME reprogramming in HNSCC.

DOI: https://doi.org/10.1371/journal.pgen.1012107
Cytokine Growth Factor Rev. 2026 May 17. pii: S1359-6101(26)00040-7. [Epub ahead of print]90 26-38

Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.

Jing Hu, Jiayue Qiu, Tommy Chen, Bingfei Yu.

  Adoptive T cell therapy has transformed the treatment of hematologic malignancies but fails to control solid tumors, where T cell dysfunction and an immunosuppressive tumor microenvironment (TME) remain the central barriers. Cytokines are essential regulators of both T cell fate and the TME, making cytokine engineering a key lever for overcoming these limitations. Here we review recent advances in intrinsic strategies that embed cytokine support directly into the engineered T cell product and extrinsic strategies that deliver cytokines to the tumor site to remodel the TME, providing a comprehensive analysis to guide rational strategy selection and combination. We further highlight synthetic cytokine and receptor designs that induce novel T cell states beyond the boundaries of natural T cell biology. Finally, we propose virtual cytokine networks as a framework for predicting patient-specific immune cascades triggered by any designed cytokine intervention, providing a path toward personalized cytokine-guided adoptive T cell therapy.

Keywords:  Adoptive T cell therapy; CAR-T therapy; Cancer immunotherapy; Cytokine engineering; Synthetic cytokine receptor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2026.05.002
Cell Death Dis. 2026 May 29.

Ripk2 promotes CD8+ T cell inactivation and hepatocellular carcinoma progression through Myb/Cxcl9 and Pax5/Adpgk signaling pathways.

Zengbin Wang, Huahui Yu, Le Yu, Mengxin Liu, Xuemei Huang, Linqing Wu, Wenhao Teng, Shiguang Chen, Zhuting Fang.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, characterized by complex pathogenesis and immune escape mechanisms. The tumor immune microenvironment plays an increasingly recognized role in tumorigenesis, progression, and treatment. Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) plays a pivotal role in inflammatory responses and immune regulation. This study aimed to investigate the role of Ripk2 in the HCC immune microenvironment, particularly its impact on macrophage function, using a macrophage Ripk2 knockout mouse model (Ripk2CKO), single-cell sequencing analysis (scRNA-seq) and flow cytometry (FCM). We found that inhibiting or deleting Ripk2 altered the intratumoral microbiota within macrophages, significantly increasing the abundance of Streptomyces collinus (Sc). This alteration not only prompted a metabolic shift in macrophages but also significantly upregulated the transcription factor Myb expression, promoting Cxcl9 secretion, thereby enhancing CD8+ T cell infiltration, activity, and proliferation. Furthermore, Ripk2 was found to promote lactate production via the Pax5/Adpgk pathway, leading to CD8+ T cell dysfunction and forming an immunosuppressive feedback loop in HCC. Combining a Ripk2 inhibitor (GSK583) with a PD-1/PD-L1 inhibitor (BMS202) reduced the hepatotoxicity of BMS202 monotherapy and improved therapeutic efficacy. In conclusion, this study provides new insights into the role of Ripk2 in the HCC immune microenvironment and lays an experimental foundation for the development of Ripk2-targeted immunotherapy strategies.

DOI: https://doi.org/10.1038/s41419-026-08849-0
Medicina (Kaunas). 2026 Apr 27. pii: 826. [Epub ahead of print]62(5):

Comparison of Stromal Tumor-Infiltrating Lymphocyte (sTIL) Levels and Clinicopathological Features in Neoadjuvant-Naive HER2-Low and HER2-Negative Primary Breast Cancers.

Mümin Emiroğlu, Esra Canan Kelten Talu, Cem Karaali, Olçun Ümit Ünal, Mihriban Erdoğan.

  Background and Objective: The clinical success of novel antibody-drug conjugates has led to the identification of a new subgroup within traditionally HER2-negative breast cancers, termed 'HER2-low.' The aim of this study was to investigate the clinicopathological differences between HER2-low and HER2-negative groups in neoadjuvant-naive primary breast cancer patients, with a specific focus on stromal tumor-infiltrating lymphocyte (sTIL) density. Materials and Methods: The study included 731 neoadjuvant-naive invasive breast cancer patients. Tumors were classified as HER2-negative (IHC 0) and HER2-low (IHC 1+ or 2+/ISH-negative). sTIL levels were evaluated following the International TILs Working Group guidelines. Results: The HER2-low group (38.7%) demonstrated significantly higher histological grade (p = 0.033) and higher sTIL density (p = 0.006) compared to the HER2-negative group. A stepwise increase in sTIL rates was observed parallel to the HER2 immunohistochemical score (0 → 1+ → 2+) (p = 0.015). The HER2-low/hormone receptor (HR)-negative subgroup exhibited the highest sTIL density (median 35%). No statistically significant difference in overall or disease-free survival was found between the groups. Conclusions: HER2-low breast cancers were associated with a more immunogenic tumor microenvironment compared to HER2-negative tumors. This robust immune infiltration may offset the higher histological grade observed in the HER2-low cohort, potentially explaining the comparable survival outcomes. These findings provide a biological rationale for exploring the synergy between novel antibody-drug conjugates and immune checkpoint inhibitors, particularly in the highly immunogenic HER2-low/HR-negative subgroup.

Keywords:  HER2-low; antibody-drug conjugates; breast cancer; prognosis; stromal tumor-infiltrating lymphocytes; tumor microenvironment

DOI:  https://doi.org/10.3390/medicina62050826
Vaccines (Basel). 2026 Apr 30. pii: 402. [Epub ahead of print]14(5):

Reinvigorating the Cancer-Immunity Cycle by Intratumoral Administration of Conventional Dendritic Cells in Melanoma and Other Solid Tumors: A Narrative Review.

Manon Vounckx, Iris Dirven, Cleo Bertels, Julia Katharina Schwarze, Xenia Geeraerts, Sandra Tuyaerts, Anaïs Boisson, Karen Willard-Gallo, Bart Neyns.

  Dendritic cells (DCs) are central to cancer immunity, orchestrating both innate and adaptive immune responses. In melanoma and other solid tumors, however, their function is often impaired within the tumor microenvironment (TME), leading to weakened antitumor immunity and diminished responses to immune checkpoint inhibitors (ICIs) and adoptive tumor-infiltrating lymphocyte (TIL) therapy. Among the various cell-based immunotherapy approaches, DC therapy-particularly using blood-derived conventional DCs (cDCs)-holds considerable promise. Compared with traditional monocyte-derived DCs (moDCs), cDCs exhibit superior antigen processing and cross-presentation capacities. The therapeutic application of cDCs was initially pioneered in vaccine strategies involving ex vivo antigen loading and maturation, followed by administration to lymph nodes. More recently, intratumoral (IT) cDC immunotherapy has emerged as a strategy to reinvigorate the cancer-immunity cycle by engaging the full repertoire of tumor-associated antigens while limiting systemic toxicity. This review discusses the underlying biological mechanisms and summarizes the clinical outcomes of IT DC therapy in cancer. Notably, combination approaches incorporating IT cDCs with ICIs, oncolytic viruses, synthetic adjuvants, radiation, or cryotherapy are emerging as promising strategies to overcome both primary and acquired resistance to ICI monotherapy. Collectively, these findings highlight the potential of integrating IT cDC therapy with complementary immunotherapies in next-generation, cross-tumor treatment strategies.

Keywords:  combinatorial cancer immunotherapy; dendritic cell therapy; immune checkpoint inhibition; intratumoral therapy

DOI:  https://doi.org/10.3390/vaccines14050402
Int Immunol. 2026 May 29. pii: dxag027. [Epub ahead of print]

Mitochondrial Transfer-Driven Immune Evasion in the Tumor Microenvironment.

Li Zhu, Yosuke Togashi.

  The tumor microenvironment (TME) is a complex landscape where metabolic interactions significantly dictate antitumor immunity. Immune evasion in cancer is typically discussed in terms of inhibitory receptors and ligands, suppressive cytokines, defective antigen presentation, and metabolic competition. However, recent evidence reveals that intercellular mitochondrial transfer adds a new mechanism of immune evasion in the TME. The mitochondrial fitness of T cells is central to sustained effector function, memory formation, and responsiveness to immune checkpoint blockade. Tumor cells can act as pathogenic mitochondrial donors, transferring functional or dysfunctional mitochondria to neighboring T cells via tunneling nanotubes and extracellular vesicles. This process involves a mitophagy imbalance that leads to the homoplasmic replacement of endogenous mitochondria, thereby driving T-cell senescence, impairing memory formation and long-term antitumor function, and ultimately weakening cancer immunosurveillance. Overall, mitochondrial transfer should be considered a new part of the tumor immune evasion framework. It also provides new therapeutic opportunities for improving cancer immunotherapy.

Keywords:  Mitochondrial transfer; T-cell exhaustion; immune checkpoint blockade; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/intimm/dxag027
Front Immunol. 2026 ;17 1832715

Immunoscore and beyond: evolution and clinical integration of immune contexture-based biomarkers across solid tumours.

Esteban Orenes-Piñero, Silverio Ros-Martínez, José Luis Alonso-Romero, Juan Antonio Ortega-García.

  The tumour immune microenvironment is increasingly recognised as a critical determinant of cancer progression, prognosis, and therapeutic response, challenging the sufficiency of anatomy-based staging systems such as TNM. The Immunoscore (IS), originally validated in colorectal cancer, provides a standardised, spatially resolved assessment of CD3+ and CD8+ T cells within the tumour core (TC) and invasive margin (IM). Expanding upon this framework, adapted and modified IS models, as well as computational and imaging-based surrogates, have been investigated across multiple solid malignancies, including non-small-cell lung cancer, hepatocellular carcinoma, head and neck cancers, gastric cancer, melanoma, and bladder cancer. This review synthesises the current evidence, emphasising both the translational potential and methodological heterogeneity of IS-based approaches. High IS or adapted scores generally correlate with improved survival and may refine risk stratification, complementing conventional TNM staging. However, inter-study variability limits comparability and reproducibility. Retrospective designs, single-centre cohorts, limited external validation, and potential overfitting in computational models further constrain the strength of evidence. Biological context dependency, immune-exclusion phenotypes, and the dynamic evolution of the tumour immune landscape complicate interpretation, underscoring that high immune cell density does not universally equate to effective antitumour immunity. Overall, the IS and related immune-contexture classifiers constitute a biologically grounded framework that bridges tumour immunology and clinical oncology. While promising, widespread clinical implementation requires methodological harmonisation, prospective validation, and integration with genomic, systemic, and imaging biomarkers. By highlighting both achievements and current limitations, this review provides a balanced perspective on the potential and challenges of translating immune contexture-based metrics into precision oncology.

Keywords:  Immunoscore; bladder cancer; gastric cancer; head and neck squamous cell carcinoma; hepatocellular carcinoma; melanoma; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fimmu.2026.1832715
J Immunol. 2026 May 14. pii: vkag108. [Epub ahead of print]215(5):

PI3Kδ inhibition alters CD8 T cell differentiation and reprograms the tumor microenvironment following adoptive immunotherapy.

Alexandrea Turnquist, Azka Javaid, Owen M Wilkins, Fred Kolling Iv, Patricia A Pioli, Chrystal M Paulos, Hildreth Robert Frost, Edward J Usherwood.

  T cell exhaustion remains a significant barrier to effective adoptive cell therapy in solid tumors. Here, we demonstrate that in vitro treatment with the PI3Kδ inhibitor CAL-101 generates T cells with enhanced stemness and metabolic fitness. These cells show increased mitochondrial dependence and spare respiratory capacity while maintaining normal basal metabolism. Under chronic antigen stimulation, CAL-101-treated T cells, including human T cells, resist terminal exhaustion and maintain stem-like properties. Using single-cell RNA sequencing and spatial transcriptomics of B16 melanoma tumors, we found that CAL-101-treated T cells preferentially differentiate into progenitor exhausted T cells within the tumor microenvironment. These cells demonstrate enhanced tumor infiltration and upregulate the Cxcl10/Cxcr3 signaling axis. The tumor microenvironment of tumors containing CAL-101-treated T cells show reduced glycolysis, oxidative phosphorylation, and proliferation, while exhibiting increased proinflammatory signaling and decreased presence of immunosuppressive tumor-associated macrophages. Single-cell analysis reveals that the CAL-10-treated T cells concurrently increase oxidative phosphorylation, proliferation, and immune signaling pathways. Mechanistically, CAL-101-treated T cells maintain high expression of stemness-associated genes (Tcf7, Slamf6) while resisting expression of genes associated with terminal exhaustion (Tim3, Mt1/2). These findings reveal the mechanisms behind how PI3Kδ inhibition generates T cells capable of establishing and maintaining an antitumor immune response, suggesting a promising strategy for improving adoptive cell therapy outcomes in solid tumors.

Keywords:  T cells; cancer; cytotoxic; memory; tumor immunity

DOI:  https://doi.org/10.1093/jimmun/vkag108
Nat Commun. 2026 May 23.

PD-1 regulates latent effector differentiation of thymic cytotoxic CD8+ T cells.

Zhiming Mao, Jacob B Hirdler, Joanina K Gicobi, Li Ding, Mark A Maynes, Michelle A Hsu, Emilia R Dellacecca, Wenjing Zhang, Jacob J Teske, Ying Li, Aubrey Y Liew, Geoffrey Zhao, Adrian T Ting, Virginia M Shapiro, Fabrice Lucien-Matteoni, Henrique Borges da Silva, Daniel D Billadeau, Haidong Dong.

Durable T cell immunity against cancer depends on the continual replenishment of effector CD8⁺ T cells. Thymic output has been associated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, whether CD8⁺ T cells acquire effector potential within the thymus, and how thymic output of effector CD8⁺ T cells contribute to peripheral tumor immunity, remain unclear. In this study, we discover that thymic single-positive (SP) CD8⁺ T cells undergo latent effector differentiation following thymic selection, but this process is subject to PD-1 regulation. We further demonstrate that PD-1 limits the contribution of thymic output of CD8⁺ T cells in shaping the TCR repertoire within the tumor tissues for tumor immunosurveillance. Although PD-1 inhibition facilitates the expansion of effector CD8⁺ T cells in the periphery, these cells gradually lose antitumor activity within tumors due to accelerated exhaustion in the absence of PD-1. Thus, while latent effector differentiation of thymic CD8⁺ T cells enables a rapid response to malignant cells in the periphery, PD-1 restrains this process to prevent overt or terminal effector differentiation, which may compromise balanced and durable peripheral immunity.

DOI: https://doi.org/10.1038/s41467-026-73392-7
Front Oncol. 2026 ;16 1810903

Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges.

Wenfang Hu, Zhongyu Zhang, Mengyao Pan, Weiye Wang, Zibing Wang.

  T-cell receptor-engineered T-cell (TCR-T) therapy has emerged as a promising strategy for solid tumors because it enables recognition of intracellular antigens presented by human leukocyte antigen (HLA) molecules, thereby extending targetability beyond cell-surface proteins. However, its clinical activity remains inconsistent because of HLA restriction, heterogeneous antigen expression, unstable antigen presentation, and an immunosuppressive tumor microenvironment. In this review, we summarize the biological basis of TCR-T therapy in solid tumors, including peptide-HLA recognition, target selection, antigen-presentation barriers, and mechanisms of tumor-cell killing. We then review current clinical progress across major solid tumor types, highlighting meaningful responses in selected biomarker-defined settings while noting that efficacy in many epithelial cancers remains limited. Current evidence further indicates that target recognition alone is insufficient for durable tumor control; sustained benefit also depends on preserved antigen presentation, effective tumor trafficking, resistance to suppressive signals, and maintenance of T-cell fitness. We also discuss emerging strategies to improve therapeutic performance, including precision receptor engineering, multi-HLA target development, microenvironment-focused armoring, and manufacturing optimization. Overall, TCR-T therapy provides a compelling framework for solid-tumor treatment, but broader and more durable benefit will require integrated advances in target selection, safety design, and cellular engineering.

Keywords:  TCR-T therapy; adoptive cell therapy; antigen presentation; peptide–HLA; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2026.1810903