bims-tuinly 2026-06-21 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–06–21
35 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

PD-1 and TIGIT coexpression enables selective enrichment of clonally expanded tumor-reactive CD8 T cells for melanoma TIL therapy.
Cellular immunotherapy in melanoma: the next frontier in cancer treatment.
Target receptor expression dictates the selective intra-tumoral targeting of CD8+ T cells by eciskafusp alfa in matched PBMCs and TILs from CPI-naïve patients.
Advances in immunotherapies in ovarian cancer.
High SOX17 expression is correlated with favorable prognosis and CD8(+) TILs expression in patients with pancreatic cancer after curative resection.
Tumor-infiltrating lymphocytes display prognostic signatures associated with chemotherapy response in TNBC patients.
The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.
CRISPR-screen informed engineered T cell therapies.
Impact of PD-1+Tim-3+CD8+ T cells in pretreatment tumors on chemotherapy responses in esophageal cancer.
Major histocompatibility complex II serves as a prognostic biomarker in resectable pulmonary sarcomatoid carcinoma: development of a prediction model.
siRNA-mediated silencing of placenta-specific protein 1 (PLAC1) alters CD4+, CD8+, and regulatory T cells in a murine colon cancer model.
Docetaxel enhances Vβ-directed T-cell activation and antitumor immunity mediated by a bifunctional TCR agonist in breast and prostate cancer models.
Predictive Biomarkers for Immune Checkpoint Inhibitor Efficacy: Challenges, Innovations, and a Pathway to Precision Medicine in the Era of Cancer Immunotherapy.
Understanding cardiac toxicity and immune responses to thoracic radiation therapy in non-small cell lung cancer - implications for future research.
Single-cell transcriptomic profiling reveals innate-like cytotoxic intraepithelial lymphocyte expansion during Salmonella Enteritidis infection in chickens.
Activation of tumor-specific CD8+ T cells prior to radiopharmaceutical therapy improves antitumor response.
Block, clear, and boost: a novel therapeutic framework for targeting intercellular mitochondrial transfer in Cancer immunotherapy.
Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
Tumor-infiltrating CD8+Ki-67+ and CD8+LAG-3+ T cells are associated with improved patient survival in retroperitoneal dedifferentiated liposarcomas and leiomyosarcomas.
Comprehensive characterization and prognostic analysis of multifocal intracranial germ cell tumors.
Mitochondrial DNA in Lung Cancer: from biology to clinical implications.
Engineering potent TILs from an immune-excluded tumor: Insights from chondrosarcoma.
Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in Colorectal Cancer.
Bridging the Gap: The Emerging Role of memory CD8+ T Cells in Fibrotic Interstitial Lung Disease.
Ovarian localization drives IL-7R-dependent CD8 coreceptor expression in peripheral double-negative T cells.
Programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) in multiple myeloma.
Clinical efficacy of anti-PD-1 immunotherapy with localized non-ablative irradiation against metastatic lymph node in patients with metastatic gastric cancer.
Single-Cell Reveal GALNT7-Dependent Ferroptosis Suppression as a Mechanism of Immunotherapy Resistance in Non-Small Cell Lung Cancer.
Can combined biochemical and radiological responses enhance prognostic assessment after neoadjuvant therapy for locally advanced gastric cancer? A multicenter real-world study.
Tumor immune microenvironment states inferred from TLS-associated immune-cell composition stratify prognosis in hepatocellular carcinoma.
TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy.
Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.
Chemical priming potentiates mesothelin-targeting chimeric antigen receptor-engineered NK-92 antitumor activity by improving tumor trafficking and cytotoxic killing dynamics.
Rejuvenated Hematopoietic Stem and Progenitor Cell-Engineered CAR-Armored Natural Killer T Cells for Malignant Pleural Mesothelioma.
A spatial immune scoring system based on the tumor microenvironment features improves prognostic stratification in lung adenocarcinoma.

J Transl Med. 2026 Jun 17.

PD-1 and TIGIT coexpression enables selective enrichment of clonally expanded tumor-reactive CD8 T cells for melanoma TIL therapy.

Kathleen Ducoin, Tiffany Beauvais, James Goward, Mawuena Ahondo, Sylvia Lambot, Aurélie Mordelet, Anaïs Daminette, Morane Thabot, Jixin Deng, Song Tian, Samuel Rulli, Gaëlle Quereux, Amir Khammari, Nathalie Labarrière.

   BACKGROUND: Although anti-PD-1 antibodies are approved as first-line treatment for patients with metastatic melanoma (MM), many patients remain resistant. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) represents a promising alternative or complementary strategy, but heterogeneous clinical response rates indicate that TIL-ACT still requires optimization, particularly through enrichment of tumor-specific T lymphocytes. We recently identified a circulating CD8⁺ T-cell population, termed DPOS, defined by PD-1 and TIGIT coexpression, whose frequency correlates with anti-PD-1 efficacy in MM patients. Because these activated CD8⁺ T cells are enriched in melanoma antigen-specific lymphocytes, we hypothesized that this biomarker combination could enable the selective isolation of TILs with high therapeutic potential.
METHODS: Deep immunophenotyping, T-cell receptor (TCR) sequencing, in vitro functional assays, and in vivo patient-derived xenograft models were used to characterize and evaluate the antitumor reactivity of the DPOS subset. A clinically compatible workflow for selective isolation and expansion of DPOS TILs was developed using flow cytometry sorting and ex vivo expansion.
RESULTS: DPOS TILs displayed high expression of activation, costimulatory, tissue residency, and pre-exhaustion markers, consistent with an effector-memory phenotype, while maintaining proliferative capacities similar to other CD8⁺ TILs. TCR sequencing and ELISpot assays demonstrated that the DPOS subset is enriched in clonally expanded tumor antigen-specific T cells, with limited overlap between dominant DPOS clonotypes and those from the remaining CD8⁺ TIL compartment. Co-culture assays against autologous tumor cell lines demonstrated that DPOS TILs mediate stronger tumor recognition, characterized by increased cytotoxicity, cytokine secretion, and proliferation following antigen encounter. These functional advantages translated into improved tumor control in two patient-derived xenograft models.
CONCLUSION: PD-1⁺TIGIT⁺ CD8⁺ TILs define a distinct tumor-reactive population within human melanoma lesions. Our findings support the use of PD-1/TIGIT coexpression as a clinically applicable strategy to enrich functionally tumor-reactive CD8⁺ T cells and provide a rationale for biomarker-guided optimization of TIL-based adoptive cell therapy in melanoma.

Keywords:  Adoptive cell transfer; Immunotherapy; Melanoma; Tumor infiltrating lymphocytes; Xenograft models

DOI:  https://doi.org/10.1186/s12967-026-08459-6
J Exp Clin Cancer Res. 2026 Jun 18. pii: 139. [Epub ahead of print]45(1):

Cellular immunotherapy in melanoma: the next frontier in cancer treatment.

Anna-Lena Wien, Angeliki Stamtsis-Datsi.

  Therapy-resistant melanoma remains a major clinical challenge despite advances with immune checkpoint inhibitors and targeted therapies, as most patients ultimately exhibit primary or acquired resistance and progress through multiple toxic treatment lines with limited durable benefit. This resistance reflects not only T-cell dysfunction but also a profound quantitative deficit of tumor-reactive lymphocytes, compounded by myeloid- and Treg-mediated immunosuppression, impaired antigen presentation, and tumor dedifferentiation programs generating a cold tumor microenvironment. Cellular immunotherapies aim to overcome these barriers by supplying or priming new tumor-reactive repertoires while reshaping the tumor microenvironment and restoring durable immunity. Dendritic-cell vaccines safely induce broad, long-lived responses but show modest activity as monotherapy in advanced disease. Tumor-infiltrating lymphocyte therapy directly replaces the missing tumor-specific compartment and has demonstrated clinically meaningful response rates in checkpoint-refractory melanoma, though at the cost of complex, intensive manufacturing and conditioning requirements. Genetically engineered TCR-T and CAR T/CAR NK therapies provide programmable specificity but remain constrained by antigen selection, toxicity risks, and limited persistence in solid tumors. NK-cell platforms offer HLA-independent, off-the-shelf potential but require further optimization for trafficking, persistence, and resistance to suppression. Overall, rational combinations - particularly DC-priming integrated with adoptive cell therapy - represent the most promising path to durable tumor control in treatment-refractory melanoma.

Keywords:  Adoptive T cell transfer; CAR NK cells; CAR T cells; Immunotherapy; Tumor-infiltrating Lymphocytes

DOI:  https://doi.org/10.1186/s13046-026-03762-y
Front Immunol. 2026 ;17 1843841

Target receptor expression dictates the selective intra-tumoral targeting of CD8+ T cells by eciskafusp alfa in matched PBMCs and TILs from CPI-naïve patients.

Amrita Manchala, Eleni Maria Varypataki, Jehad Charo, Pablo Umaña, Christian Klein, Laura Codarri Deak.

   Introduction: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have shown considerable promise as a therapeutic modality in oncology. Despite their ability to target stem-like CD8+ T cells and give rise to exhaustion-fated effector CD8+ T cells, a significant subset of patients do not respond or eventually develop resistance, highlighting the need for more efficacious therapies. Eciskafusp alfa (PD1-IL2v) is a novel immunocytokine, engineered for avidity-driven, cis-delivery of IL-2R agonism to PD-1+ cells.
Methods: This study provides a comprehensive ex-vivo characterization of PD1-IL2v's target landscape using matched peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) from patients across seven solid tumor indications.
Results: We confirmed that the TIL compartment is significantly enriched with both stem-like CD8+ T cells and immunosuppressive regulatory T cells (Tregs). Notably, PD-1 receptor density was increased up to three-fold on CD8+ TILs compared to PBMCs, establishing the basis for preferential intra-tumoral targeting. Ex-vivo assays demonstrated that PD1-IL2v preferentially targets CD8+ TIL subsets (stem-like and effector) over Tregs. This preferential targeting translated into superior biological activity, with PD1-IL2v inducing higher STAT5 phosphorylation (STAT5-P) in stem-like and effector CD8+ T cells compared to Tregs, confirming the intended cis-targeting and enhanced IL-2R agonism.
Discussion: These findings provide translational validation for PD1-IL2v's mechanism, demonstrating selective intra-tumoral immune stimulation while minimizing Treg activation. This characterization identifies PD-1 receptor density and subset prevalence as critical factors for drug activity and represents potentially useful biomarkers for predicting patient responsiveness and guiding patient selection.

Keywords:  IL-2R agonism; cis-targeting; eciskafusp alfa; immunocytokine; preferential targeting; receptor density; stem-like CD8+ T cells; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fimmu.2026.1843841
J Immunother Cancer. 2026 Jun 19. pii: e014656. [Epub ahead of print]14(6):

Advances in immunotherapies in ovarian cancer.

Ruveyda Ayasun, Dmitriy Zamarin.

  Ovarian cancer (OC) remains one of the deadliest gynecologic malignancies, and, despite the presence of tumor-infiltrating lymphocytes (TILs) in nearly half of cases, immune checkpoint inhibitors have shown only modest clinical benefit. These observations have stimulated interest in antigen-directed immunotherapies, including adoptive cell therapies (chimeric antigen receptor T cell, TIL therapy), bispecific antibodies, cancer vaccines, cytokine-based agents, and antibody-drug conjugates. Multiple targets, such as mesothelin, folate receptor-α, HER2, MUC16, EpCAM, and claudin-6, are currently under clinical investigation. In this review, we summarize the current landscape of immunotherapy in OC and examine the biological and clinical factors that have limited therapeutic efficacy to date. We also discuss emerging strategies aimed at overcoming resistance, including rational combinations and biomarker-driven approaches. Finally, we highlight the critical role of integrated genomic and immune profiling to elucidate mechanisms of response and resistance and to guide the next generation of immunotherapeutic strategies for OC.

Keywords:  Immunotherapy; Ovarian Cancer; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-014656
Transl Oncol. 2026 Aug;pii: S1936-5233(26)00196-8. [Epub ahead of print]70 102859

High SOX17 expression is correlated with favorable prognosis and CD8(+) TILs expression in patients with pancreatic cancer after curative resection.

Jun Yu, Yuan Pan, Yi Chen, Zhihui Shu, Lin Ma, Bin Wu, Jingdong Li, Jianshui Li, Chuan Lan.

   OBJECTIVE: The SRY-box transcription factor 17 (SOX17) plays a critical role in tumorigenesis and tumor progression and reshaping the tumor immune ecosystem in several cancer types, but its role in pancreatic cancer (PC) remains unknown.
METHODS: A total of 168 patients with PC who underwent curative resection were consecutively enrolled, and immunohistochemical (IHC) staining was performed, followed by Kaplan-Meier and Cox proportional hazards regression analyses. Meanwhile, specific markers of cancer-associated fibroblasts (CAFs) and tumor-infiltrating lymphocytes (TILs) and PD-L1 expression were detected by IHC staining, and their correlation with SOX17 were evaluated. Finally, single-cell and bulk RNA-seq analyses of public datasets were used to validate the expression profile of SOX17 in PC.
RESULTS: The Kaplan-Meier curve showed that high SOX17 expression was correlated with a longer overall survival (OS) and disease-free survival (DFS) in patients with PC. Univariate (hazard ratio [HR] = 0.593, P = 0.005 for OS; HR = 0.602, P = 0.012 for DFS) and multivariate (HR = 0.662, P = 0.042 for OS; HR = 0.602, P = 0.036 for DFS) Cox regression analyses demonstrated that high SOX17 expression was an independent favorable prognostic factor. The correlation analysis showed that SOX17 expression was correlated with the expression of CD8+ TILs (P = 0.012) and FAP+ CAFs (P = 0.011). The correlations between SOX17 and CD8+ TILs were validated by multiple algorithms through single-cell and bulk RNA-seq analyses.
CONCLUSION: The present study demonstrates that SOX17 serves as a significant prognostic marker and reflects the tumor immune ecosystem in pancreatic cancer.

Keywords:  CD8+ tumor-infiltrating lymphocytes (TILs); Cancer-associated fibroblasts (CAFs); Pancreatic cancer; Prognostic factor; The SRY-box transcription factor 17 (SOX17)

DOI:  https://doi.org/10.1016/j.tranon.2026.102859
iScience. 2026 Jun 19. 29(6): 116295

Tumor-infiltrating lymphocytes display prognostic signatures associated with chemotherapy response in TNBC patients.

Shayantan Banerjee, Vijay K Tiwari, Karthik Raman, Mohammad Inayatullah.

  Triple-negative breast cancer (TNBC) is an aggressive subtype often resistant to neoadjuvant chemotherapy (NAC), and tumor-infiltrating lymphocytes (TILs) are important predictors of response. Using single-cell RNA sequencing datasets of pre-treated TNBC tumors, we identified an 80-gene TIL-specific signature that captures immune activation and stratifies tumors by TIL abundance. Pathway analysis showed enrichment of immune-regulatory programs, including allograft rejection, consistent with adaptive immune activity. Validation across single-cell and bulk datasets linked the signature to favorable response and relapse-free survival. A multi-stage feature selection pipeline refined the panel to 30 genes, achieving strong prediction of pathological complete response versus residual disease across eleven independent TNBC cohorts (n = 680; mean area under the ROC curve [AUROC] = 0.77). Network analysis identified consensus hub genes, including CD8A, LCK, and CTLA4, central to T cell signaling. Regulatory analysis revealed a conserved set of TIL-associated transcription factors, supporting an immune program with clinical utility in TNBC stratification and therapeutic targeting strategies.

Keywords:  Bioinformatics; Cancer; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.116295
Front Immunol. 2026 ;17 1847986

The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.

Qiang Yang, Shaobin Wang, Fanlin Liu, Yongli Yu, Hai Zhao.

  The advent of cancer immunotherapy has fundamentally restructured the oncological paradigm, moving away from agents that directly target tumor cell kinetics toward strategies that empower the host immune system to recognize and eliminate malignancy. Central to this revolution is the cytotoxic T lymphocyte (CTL), now harnessed as a potent "living drug" through engineered and naturally selected modalities. This review provides a critical, in-depth examination of the three dominant pillars of T cell-driven therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and T Cell Engagers (TCEs). We dismantle the molecular mechanisms defining each approach, contrasting the synthetic, major histocompatibility complex (MHC)-independent signaling of CAR-T cells with the diverse, MHC-restricted TCR repertoire of TILs, and the transient, pharmacologic bridging provided by bispecific TCEs. While CAR-T therapy has achieved historic success in hematologic malignancies, its translation to solid tumors is severely compromised by the hostile tumor microenvironment (TME), characterized by metabolic insulation, physical exclusion, and profound immunosuppression. Conversely, TIL therapy offers a polyclonal strategy tailored for solid tumors but is hindered by complex biomanufacturing logistics and variable tumor immunogenicity. TCEs promise off-the-shelf accessibility but face challenges regarding persistence and on-target/off-tumor toxicity. Beyond clinical outcomes, we explore the pathophysiological underpinnings of resistance, including antigen escape mechanisms and T cell exhaustion programs. Finally, we posit that the future of curative regimens lies in rational combinatorial strategies-integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses-to overcome the multifaceted defenses of solid tumors.

Keywords:  CAR T-cells; adoptive cell therapy; antigen escape; bispecific T cell engagers; immunosuppression; synthetic biology; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3389/fimmu.2026.1847986
Front Immunol. 2026 ;17 1839064

CRISPR-screen informed engineered T cell therapies.

Karrie Wong, Conor Calnan, Micah J Benson.

  Adoptive T cell therapies can deliver curative responses for refractory patients with B cell malignancies, yet clinical activity in solid tumors remains inconsistent. Tumor-intrinsic barriers dominating this inconsistency include the immunosuppressive solid tumor microenvironment (TME) imposing chronic inhibitory cues to T cells and the scarcity of patient-shared and uniformly expressed tumor-restricted antigens for T cells to target. CRISPR-based forward genetics screens enable mapping of the functional genome regulating T cell anti-tumor activity. Here, we review recent insights from pooled CRISPR knockout screens in T cells to define convergent targets and pathways regulating T cell anti-tumor function and align the pharmacology of engineered T cells with sequential barriers they encounter within the TME. We additionally propose a framework for CRISPR screen-enabled target prioritization and present an example of how these principles can be applied to the functional enhancement of T cells through TIL (Tumor Infiltrating Lymphocyte) therapy, which utilizes a patient's personalized immune response against solid tumor antigens.

Keywords:  CRISPR; T cell; TIL; adoptive cell therapy; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2026.1839064
Cancer Immunol Immunother. 2026 Jun 18.

Impact of PD-1+Tim-3+CD8+ T cells in pretreatment tumors on chemotherapy responses in esophageal cancer.

Tomoko Sumimoto, Kei Yamamoto, Takuro Saito, Shinya Urakawa, Tomohira Takeoka, Tomoki Makino, Yukinori Kurokawa, Atsunari Kawashima, Azumi Ueyama, Hidetoshi Eguchi, Yuichiro Doki, Hisashi Wada.

  While chemotherapy has traditionally been recognized for its direct cytotoxic effects on cancer cells, increasing attention has been directed towards its capability to modulate tumor immune mechanisms. However, the majority of studies have focused on the quantitative assessment of tumor-infiltrating lymphocytes (TILs), without evaluating their functional status. Therefore, the present study investigated the pre-therapeutic exhaustion status of TILs and its impact on the efficacy of neoadjuvant chemotherapy (NAC) in patients with esophageal squamous cell carcinoma (ESCC). TILs were isolated from 60 endoscopic biopsy samples from ESCC patients before NAC. The proportion of CD8+ TILs co-expressing PD-1 and Tim-3 was evaluated using flow cytometry. Their functional status was assessed by examining the expression of exhaustion markers (TOX, LAG-3, CD39), cytotoxic molecules (granzyme B, perforin), and cytokines (IFN-γ, TNF-α). A cytotoxic assay was also performed to evaluate their direct killing capacity against anti-CD3scFv BALL-1 cells. A high proportion of PD-1+Tim-3+CD8+ TILs was significantly associated with a poor pathological response to NAC (p = 0.027) and was identified as an independent predictor of poor response in multivariate analysis (odds ratio = 4.1, 95% confidence interval = 1.1-14.7, p = 0.032). A functional analysis revealed that PD-1+Tim-3+CD8+ TILs expressed high levels of exhaustion markers and low levels of cytotoxic molecules and cytokines and also exhibited impaired cytotoxic function. The proportion of PD-1+Tim-3+CD8+ TILs decreased after NAC in responders. These results suggest the potential of a high proportion of PD-1+Tim-3+CD8+ TILs in the pre-treatment tumor microenvironment as a useful predictor of a poor NAC response in ESCC patients.

Keywords:  Esophageal cancer; Neoadjuvant chemotherapy; PD-1; T cell exhaustion; Tim-3; Tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1007/s00262-026-04303-4
Transl Lung Cancer Res. 2026 May 31. 15(5): 137

Major histocompatibility complex II serves as a prognostic biomarker in resectable pulmonary sarcomatoid carcinoma: development of a prediction model.

Hao Wang, Li Ye, Xinyue Liu, Yujie Li, Zhimin Chen, Wengang Zhang, Yujin Liu, Xuyang Chen, Wencheng Zhao, Qianqian Zhang, Runze Huang, Jialin Zeng, Shiying Chen, Yuhang Li, Lishu Zhao, Kandi Xu, Yayi He.

   Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare pulmonary malignancy, exhibiting a poor outcome even after complete resection. Major histocompatibility complex II (MHC-II) is a critical molecule in priming anti-tumor immunity, while its expression and the prognostic role in PSC have been rarely investigated. This study aimed to evaluate intratumoral MHC-II expression and assess its prognostic value in resected PSC for the development of MHC-II-based prediction models.
Methods: In this retrospective study, we enrolled 86 patients with resected PSC. Immunohistochemistry (IHC) was used to evaluate MHC-II expression. Patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (LASSO) regression was used to select predictors and construct prognostic models for progression-free survival (PFS) and overall survival (OS). Model performance was assessed using the area under the curve (AUC). Additionally, public RNA sequencing data (n=17) from Gene Expression Omnibus (GEO) were used for bioinformatics analysis.
Results: We demonstrated positive MHC-II expression on both tumor cells (22.09%) and tumor-infiltrating lymphocytes (TILs) (36.05%). Higher expression of MHC-II on both tumor cells and TILs indicated longer PFS (P=0.005 and P=0.042) and OS. The MHC-II-based prognostic models showed performance in the validation cohort with AUC exceeding 0.70 for both PFS and OS. Bioinformatics analysis suggested that samples with high MHC-II expression had higher infiltration levels of CD4+ T cells, CD8+ T cells, dendritic cells (DCs), and M1 macrophages. Meanwhile, programmed cell death protein 1 (PD-1) signaling was also upregulated in MHC-IIhigh group.
Conclusions: Our study uncovered the expression of MHC-II and its prognostic role in PSC. High expression of MHC-II might induce an inflamed tumor microenvironment (TME). And anti-PD-1 treatment might be a promising treatment for MHC-IIhigh PSC.

Keywords:  Pulmonary sarcomatoid carcinoma (PSC); major histocompatibility complex II (MHC-II); prognosis; tumor immunology; tumor microenvironment (TME)

DOI:  https://doi.org/10.21037/tlcr-2026-1-0110
Sci Rep. 2026 Jun 19.

siRNA-mediated silencing of placenta-specific protein 1 (PLAC1) alters CD4+, CD8+, and regulatory T cells in a murine colon cancer model.

Mojgan Esparvarinha, Hamid Nickho, Alireza Najafi, Maryam Keykhaee, Ali Zarezadeh Mehrabadi, Leili Aghebati-Maleki, Reza Falak, Mehdi Yousefi.

  PLAC1 has been found to be upregulated in colorectal cancer (CRC). However, its precise role and the molecular mechanisms driving CRC progression remain unclear. This study aimed to elucidate the role of PLAC1 in CRC progression and to evaluate its immunomodulatory effects using an in vivo syngeneic mouse model. Small interfering RNA (siRNA) was employed to silence PLAC1 expression in the CT26 murine colorectal cancer cell line. Gene silencing efficiency was confirmed by quantitative real-time PCR (qRT-PCR). CT26 cells were subcutaneously injected into BALB/c mice to establish an in vivo tumor model. Tumor growth was monitored, and immune responses were assessed by analyzing tumor-infiltrating lymphocytes (TILs) and splenic immune cell populations. Flow cytometry was used to characterize T cell subsets (CD3, CD4, CD8, FoxP3) and PLAC1 expression. PLAC1 knockdown was associated with a reduction in the frequency of regulatory T cells (Tregs) in both tumor and spleen. It was also associated with an increased proportion of CD3⁺CD4⁺ T cells in the spleen and CD3⁺CD8⁺ T cells in the tumor. Intratumoral administration of PLAC1-targeting siRNA was associated with reduced tumor volume, extended survival, and was associated with changes consistent with enhanced antitumor immunity in tumor-bearing mice. Silencing of PLAC1 was associated with decreased Treg frequency and increased effector T cell populations, suggesting a shift toward a less immunosuppressive tumor microenvironment. These findings may support further investigation of PLAC1 as a potential target for immunotherapeutic strategies in CRC and other malignancies expressing PLAC1.

Keywords:  Colorectal cancer (CRC); Placenta-specific protein 1 (PLAC1); Regulatory T cells; Tumor-infiltrating lymphocytes; siRNA-mediated gene silencing

DOI:  https://doi.org/10.1038/s41598-026-45740-6
Front Immunol. 2026 ;17 1850760

Docetaxel enhances Vβ-directed T-cell activation and antitumor immunity mediated by a bifunctional TCR agonist in breast and prostate cancer models.

Jonelle K Lee, Kellsye P Fabian, Ginette S Santiago-Sanchez, Francesca Rosato, Michelle R Padget, Cailyn Lee, Zhen Su, Jacques Moisan, Madan Katragadda, Jeffrey Schlom, James L Gulley, Andrew Bayliffe, James W Hodge.

   Background: STAR0602 is a selective bifunctional T cell agonist targeting Vβ6/Vβ10 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1-resistant tumors. Its murine surrogate, mSTAR1302, expands Vβ13 T cells and mediates antitumor activity. Docetaxel, beyond its cytotoxic effects, induces immunogenic modulation of tumor cells. We hypothesized that docetaxel-driven tumor sensitization would enhance susceptibility to immune-mediated killing, while mSTAR1302 would expand functional T cell subsets, resulting in coordinated antitumor responses.
Methods: The therapeutic efficacy and mechanism of action of docetaxel and mSTAR1302 combination therapy were evaluated in 4T1 triple-negative breast cancer and TRAMP-C2 prostate cancer models. Immune profiling, functional assays, and CRISPR-mediated gene knockdown were used to define mechanisms of response.
Results: Combination therapy significantly reduced tumor burden and improved survival compared to monotherapies in both models. Docetaxel induced immunogenic modulation characterized by upregulation of MHCI, FAS, and TRAIL-R2, enhancing tumor susceptibility to immune-mediated lysis. Mechanistically, TRAIL-R2 expression contributed substantially to antitumor activity, as knockdown attenuated therapeutic efficacy. mSTAR1302 expanded Vβ13+ CD4+ and CD8+ tumor-infiltrating lymphocytes and promoted antigen-specific T cell responses. Depletion studies demonstrated that CD4+ T, CD8+ T, and NK cells collectively mediated the antitumor effects of combination therapy.
Conclusions: These findings identify a mechanistic axis in which docetaxel-induced tumor sensitization via TRAIL-R2 cooperates with Vβ-targeted T cell expansion to drive coordinated immune-mediated tumor regression. This work supports the clinical evaluation of STAR0602 in combination with chemotherapy and highlights TRAIL-R2-mediated tumor sensitization as a mechanistically defined strategy to enhance immunotherapy efficacy in immune-excluded tumors.

Keywords:  TcE (T-cell engager); breast cancer; combination immune therapies; docetaxel; prostate cancer

DOI:  https://doi.org/10.3389/fimmu.2026.1850760
Clin Chem. 2026 Jun 18. pii: hvag062. [Epub ahead of print]

Predictive Biomarkers for Immune Checkpoint Inhibitor Efficacy: Challenges, Innovations, and a Pathway to Precision Medicine in the Era of Cancer Immunotherapy.

Matthew Lee, Jeffrey A SoRelle, Arun Everest-Dass, David E Gerber, Mitchell S von Itzstein.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed oncology practice. However, treatment response remains heterogeneous, rendering predictive biomarkers critical for optimal patient care. The 3 established biomarkers, programmed death-ligand 1, tumor mutational burden (TMB), and microsatellite instability-high/deficient mismatch repair, are approved and clinically validated but are modest predictors of benefit. As a result, multiple novel predictive biomarkers remain under investigation.
CONTENT: This review highlights established and investigational predictive ICI efficacy biomarkers. For established biomarkers, we describe biology, assay modalities, approved companion diagnostics, landmark studies, and notable limitations. Due to the multisystem nature of antitumor immune effects, investigational biomarkers span multiple domains, including tumor genomic biomarkers (e.g., mutational signatures, TMB, neoantigen clonality), tumor microenvironment (e.g., tumor-infiltrating lymphocytes [TILs], tertiary lymphoid structures), systemic immune biomarkers (e.g., cytokines, autoantibodies, glycoproteins, peripheral blood mononuclear cells), and the microbiome (e.g., gastrointestinal microbial diversity, responder-enriched taxa).
SUMMARY: The established biomarkers PD-L1, TMB, and microsatellite instability-high/deficient mismatch repair inform ICI use in clinical practice but have important limitations. Multiple investigational biomarkers show promise in refining patient selection and optimizing therapy. Moving forward, increased assay harmonization, prospective validation, and standardized parameters may improve performance. Composite models integrating complementary signals across domains may further individualize treatment and lead to an era of personalized cancer immunotherapy.

DOI: https://doi.org/10.1093/clinchem/hvag062
Front Oncol. 2026 ;16 1702343

Understanding cardiac toxicity and immune responses to thoracic radiation therapy in non-small cell lung cancer - implications for future research.

Zeta Chow, Ronald Charles McGarry, Jordan Miller, Waleed Fouad Mourad, Ralph Zinner, Bernard Mark Evers, Weisi Yan.

  Thoracic radiation therapy (RT) remains a mainstay treatment for locally advanced non-small cell lung cancer (NSCLC). However, recent evidence highlights significant long-term toxicities to the cardiac and immune systems, with implications for overall survival. This perspective review article examines the impact of thoracic RT on cardiac substructures and their detrimental correlation with survival. We recognized a discrepancy between major adverse cardiac events and overall survival and formulated an intriguing hypothesis linking thoracic RT to immunosuppression. Radiation to lymphocyte-rich tissues and circulating immune cells may induce profound lymphopenia, compromise immune surveillance, and reduce the efficacy of immunotherapy. We propose a dynamic exchange model between circulating lymphocytes and tumor-infiltrating lymphocytes in the context of thoracic RT and systemic immunotherapy. Herein, we highlight the importance of preserving immune system integrity and incorporating promising immune-sparing techniques in radiation planning. In summary, thoracic RT should be re-envisioned not only as an ablative local therapy, but also as a systemic immune modulator in the management of NSCLC.

Keywords:  RIHD; heart damage; iOAR; lung radiation therapy; lymphocytopenia

DOI:  https://doi.org/10.3389/fonc.2026.1702343
Front Immunol. 2026 ;17 1842283

Single-cell transcriptomic profiling reveals innate-like cytotoxic intraepithelial lymphocyte expansion during Salmonella Enteritidis infection in chickens.

Shuja Majeed, Bikas Raj Shah, Bikash Aryal, Nimra Khalid, Tae Hyun Kim, Ali Nazmi.

  Salmonella is a major foodborne pathogen that causes approximately 1.35 million infections annually in the US and remains a leading cause of poultry-associated foodborne illness. To improve chickens' resistance to this pathogen, it is important to understand the mucosal immune mechanisms that govern intestinal defense. Intraepithelial lymphocytes (IELs) positioned between intestinal epithelial cells provide frontline immune surveillance against enteric pathogens. However, a comprehensive characterization of IEL subtype responses to Salmonella infection remains incomplete. Therefore, we conducted this study to examine IEL subtypes and their mechanisms in response to a Salmonella enterica serovar Enteritidis (S. Enteritidis) challenge using a combination of spectral flow cytometry and single-cell RNA sequencing (scRNA-seq). Fifty specific-pathogen free (SPF) chicks were reared to 21 days of age and then assigned to S. Enteritidis-challenged (SE; 1.62 × 108 CFU/bird, oral gavage) or control (CN; PBS) groups (n = 25/group). On day 2 post infection (2 dpi) and 6 dpi, eight birds per group were sampled to collect liver and ceca for bacteriology and ileum for IEL acquisition. Bacteriological findings confirmed the challenge: the SE group harbored S. Enteritidis at both time points. Flow cytometry results showed that Salmonella challenge increased the proportion of TCRγδ+CD8αβ+ cytotoxic IELs at 2 dpi, as well as the overall IEL proportion at 2 and 6 dpi. Notably, scRNA-seq identified clusters of progenitor T cells that significantly expanded and innate-like cytotoxic T cells, which emerged in SE-challenged birds at 2 dpi, indicating rapid mobilization of an innate-like cytotoxic response. Integration of flow cytometry and scRNA-seq data provided evidence that cytotoxic T cells expressing CD8αβ acquire innate-like transcriptional signatures within the intestinal epithelial compartment, suggesting functional reprogramming that enables rapid antigen responses. Trajectory analysis identified a robust transcriptionally inferred trajectory from progenitor T cells through activated CD8+ T cells to innate-like CTL as the predicted terminal cluster, with quiescent stem-like resident memory T cells transcriptionally positioned as a reservoir. These findings reveal a previously uncharacterized innate-like cytotoxic IEL response as a critical early defense mechanism against Salmonella in poultry and identify self-renewing stem-like Trm cells as a reservoir for rapid IEL effector differentiation.

Keywords:  Salmonella; ScRNA-seq; chicken; intraepithelial lymphocytes; layer

DOI:  https://doi.org/10.3389/fimmu.2026.1842283
J Immunother Cancer. 2026 Jun 19. pii: e015261. [Epub ahead of print]14(6):

Activation of tumor-specific CD8+ T cells prior to radiopharmaceutical therapy improves antitumor response.

Daeun Shim, Colette Mouton, Jena E Moseman, Hansel Comas Rojas, Donghwan Jeon, Malick B Idrissou, Reinier Hernandez, Jamey P Weichert, Douglas G McNeel.

   BACKGROUND: Radiopharmaceutical therapy (RPT) delivers radiation systemically, enabling the treatment of metastatic cancers. Beyond killing tumor cells, RPT can modulate the tumor immune microenvironment. With RPTs and immunotherapies already approved or in development for prostate cancer, many preclinical and clinical studies are evaluating their use in combination. However, due to the radiosensitivity of tumor-infiltrating lymphocytes, further studies are needed to determine the effects of RPT on these cells to better inform the sequence of immunotherapies that activate T cells when given with RPT.
METHODS: E.G7-OVA tumor-bearing mice received naïve or activated OT-I CD8+T cells prior to or following the administration of RPT using 90Y-NM600. Changes in tumor growth were monitored, and tumor-infiltrating lymphocytes were evaluated for phenotypic and functional markers. The murine prostate tumor model TRAMP-C1 was used to evaluate this approach using tumor antigen-specific vaccination with 90Y-NM600.
RESULTS: Antitumor efficacy was improved if OT-I CD8+T cells were present and activated prior to 90Y-NM600 administration than if the cells were delivered after RPT. Similarly, in vivo activation of adoptively transferred OT-I CD8+T cells, using ovalbumin (OVA)-specific vaccination, prior to RPT slowed tumor growth and increased the frequency of tumor-infiltrating OVA257-264-specific CD8+T cells with effector memory phenotype and effector molecule production. Blockade of type I interferon, but not the upstream inhibition of stimulator of interferon genes, abrogated tumor growth delay resulting from the combination treatment. Tumor antigen-specific vaccination prior to 90Y-NM600 administration similarly improved antitumor outcomes in the TRAMP-C1 tumor model.
CONCLUSIONS: Our study suggests that tumor-specific CD8+T cells need to be present and activated prior to RPT to enhance antitumor outcomes. This study highlights the importance of considering the effects of RPT on tumor-infiltrating CD8+T cells when combining other T-cell activating therapies with RPT, as they may similarly display sequence-dependent antitumor outcomes.

Keywords:  Immunotherapy; Radiotherapy/radioimmunotherapy; T cell; Vaccine

DOI:  https://doi.org/10.1136/jitc-2026-015261
Int Immunopharmacol. 2026 Jun 16. pii: S1567-5769(26)00873-8. [Epub ahead of print]185 117027

Block, clear, and boost: a novel therapeutic framework for targeting intercellular mitochondrial transfer in Cancer immunotherapy.

Ruoyan Liu, Yang Yang, Zhening Wang, Zhuopeng Hu, Lei Yang, Rui Guo, Hong Wang.

Intercellular mitochondrial transfer (IMT) is emerging as a critical regulator of the tumor microenvironment, reshaping bioenergetics, signaling, and therapeutic responsiveness across the tumor-immune interface. Mitochondrial material can be exchanged within the tumor microenvironment (TME) through multiple routes, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction-associated exchange, and cell-cell fusion. The outcome of this exchange depends strongly on the quality of the transferred mitochondrial material: delivery of metabolically competent mitochondria may restore oxidative phosphorylation and effector function in T cells, whereas transfer of damaged mitochondrial cargo may amplify oxidative stress and promote terminal dysfunction. Mitochondrial quality-control mechanisms, including the PINK1-Parkin pathway and USP30-regulated deubiquitination, may critically influence how recipient cells process transferred mitochondrial material. Beyond adaptive immunity, IMT has also been implicated in innate immune compartments, including macrophages, natural killer cells, and dendritic cells. More broadly, cancer cells can acquire mitochondrial support from non-malignant partners, including neurons, adipose-derived stem cells, and endothelial cells, thereby enhancing metabolic flexibility, drug resistance, and metastatic potential in selected contexts. Based on these mechanisms, this review proposes "Block, Clear, and Boost" as a hypothesis-generating framework for organizing future studies of IMT modulation in cancer immunotherapy. The three conceptual arms refer to blocking harmful transfer, clearing damaged mitochondrial cargo, and boosting immune cells through metabolic augmentation or engineered mitochondrial donation. Importantly, this framework has not been clinically validated, and its therapeutic relevance remains to be tested in route-specific, cell-type-specific, and prospectively designed studies. To support future translational development, we discuss candidate biomarkers for patient stratification, including host mtDNA haplogroups, somatic tumor signatures (e.g., Mitochondrial Pathway Signature, MitoPS), and circulating IMT proxies. Finally, we outline challenges and future directions for evaluating IMT modulation alongside existing immunotherapies, including immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs).

DOI: https://doi.org/10.1016/j.intimp.2026.117027
J Immunol. 2026 Jun 07. pii: vkag120. [Epub ahead of print]215(6):

Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.

Paul L Lindau, Alex V Nesta, Caroline E Roe, Madelyn D Landis, Zaid Hatem, Allison E Sewell, Allison K Blount, Jackie E Bader, Reddy Anupama, W Kimryn Rathmell, Jonathan M Irish, Jeffrey C Rathmell, Kathryn E Beckermann.

  Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired antitumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation and may also indicate cellular dysfunction. Here, we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells prior to and after 3 wk on treatment with immune checkpoint inhibitors (ICIs). Peripheral blood mononuclear T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single-cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations, while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICIs was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy.

Keywords:  T cells; checkpoint inhibitor; kidney cancer; lung cancer; metabolism; mitochondria

DOI:  https://doi.org/10.1093/jimmun/vkag120
Exp Mol Pathol. 2026 Jun 17. pii: S0014-4800(26)00036-5. [Epub ahead of print]147 105057

Tumor-infiltrating CD8+Ki-67+ and CD8+LAG-3+ T cells are associated with improved patient survival in retroperitoneal dedifferentiated liposarcomas and leiomyosarcomas.

Iva Benesova, Antonia Stammberger, Jan Balko, Jessica Pablik, Andrej Ozaniak, Luise Rupp, Robert Lischke, Jürgen Weitz, Jirina Bartunkova, Rebekka Wehner, Zuzana Ozaniak Strizova, Marc Schmitz.

  Tumor-infiltrating immune cells play a fundamental role in shaping patient prognosis across many cancers. Retroperitoneal dedifferentiated liposarcomas (DDLPS) and leiomyosarcomas (LMS) are associated with poor prognosis, therefore, a deeper understanding of the immune landscape in these tumors is warranted to identify novel prognostic biomarkers and immunotherapeutic targets. In this exploratory study, we analyzed spatial organization, frequency, and proportions of CD8+ T cell (including activated, proliferating, and exhausted phenotypes), T helper, and macrophage subsets, and B cells in primary treatment-naive retroperitoneal DDLPS (n = 22) and LMS tissues (n = 10) using classical and multiplex immunohistochemistry. CD8+LAG-3+ T cells comprised the highest proportion of all analyzed CD8+ subsets. Their elevated density was associated with improved overall survival (OS). Moreover, higher density of CD8+Ki-67+ T cells was linked to better OS and tended to independently predict OS. Interestingly, enhanced density of regulatory T cells was associated with favorable OS. Densities and proportions of T cell subsets did not significantly differ between DDLPS and LMS. A lower density of M2-like macrophages (CD68+CD163+) was linked to better progression-free survival (PFS) and tended to serve as an independent prognostic factor. Invasive margin revealed distinct prognostic patterns compared to tumor core, where high levels of CD8+Ki-67+TCF1+ were linked to better PFS and elevated proportions of CD8+GrzB+ and CD3+T-Bet+ T cells were associated with inferior PFS. These findings highlight the clinical relevance of immune infiltration in retroperitoneal DDLPS and LMS. Moreover, they support the rationale for further exploration of the immune architecture for prognostic biomarkers and development of targeted immunotherapeutic strategies to improve the clinical outcomes of the patients.

Keywords:  CD8(+) T cells; Dedifferentiated liposarcoma; Leiomyosarcoma; Retroperitoneal soft tissue sarcoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.yexmp.2026.105057
BMC Neurol. 2026 Jun 15.

Comprehensive characterization and prognostic analysis of multifocal intracranial germ cell tumors.

Yi Zhang, Xinyi Chai, Yue Hu, Kan Deng, Yong Yao.

   BACKGROUND: Given the limited evidence on multifocal intracranial germ cell tumors (iGCTs)-a rare but clinically distinct entity-this study comprehensively characterizes their clinical features and identifies key prognostic factors.
METHODS: A retrospective analysis was conducted on 48 patients diagnosed with multifocal iGCTs from 2006 to 2025 in our center. Demographics, clinical presentation, MRI characteristics, pathology, treatment modalities, and survival outcomes were analyzed. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier methods. Prognostic factors were identified through univariate and multivariate analyses.
RESULTS: Median age at diagnosis was 13 years (range: 6-31), with male predominance (87.5%). The most common symptoms were diabetes insipidus (81.2%) and hemiparesis (56.2%). Significant imaging features included hemiatrophy (47.9%) and heterogeneous enhancement (68.8%). Germinoma was diagnosed in 66.7% of patients and combined chemoradiotherapy (CHT + RT) was administered to 58.3% of patients. The 10-year OS and PFS rates were 84.6% and 70.6%, respectively. In this exploratory analysis, factors associated with favorable outcomes included germinoma histology (HR = 0.06, 95% CI 0.01-0.53, P = 0.011), combined CHT + RT (HR = 0.09, 95% CI 0.01-0.76, P = 0.027), and absence of tumor-infiltrating lymphocytes (HR = 0.14, 95% CI 0.02-1.06, P = 0.050 for PFS).
CONCLUSION: Multifocal iGCTs represent a distinct clinical entity with outcomes that are poorer compared to solitary iGCTs. Germinoma, combined chemoradiotherapy, and lymphocyte infiltration may be associated with survival, warranting further investigation. These findings emphasize the importance of histology-driven, multimodal treatment strategies for optimizing outcomes in this rare disease.

Keywords:  Intracranial germ cell tumors; Multifocal; Prognostic factors

DOI:  https://doi.org/10.1186/s12883-026-05051-9
Crit Rev Oncol Hematol. 2026 Jun 18. pii: S1040-8428(26)00318-5. [Epub ahead of print] 105431

Mitochondrial DNA in Lung Cancer: from biology to clinical implications.

José Lucio-Lozada, Diddier Prada, Luiza Beato-González, Fred R Hirsch, Andres F Cardona, Norma Hernández-Pedro, Oscar Arrieta.

  Mitochondrial DNA (mtDNA) is emerging as a relevant component of the molecular landscape in non-small cell lung cancer (NSCLC). Due to its inherent vulnerability to environmental carcinogens, the mitochondrial genome accumulates alterations-such as D-loop variants and Electron Transport Chain variants- increasingly identified as potential mediators of tumor development and metabolic shifts. Recent findings highlight specific areas with potential for clinical application. In diagnostics, emerging models based on cf-mtDNA fragmentomics and tRNA-derived fragments have shown promising capabilities for early-stage detection. Prognostically, somatic variants in Complex I and specific mitochondrial lncRNA signatures have been evaluated as independent indicators of overall survival and metastatic risk. Furthermore, in regard to therapeutics, mitochondrial mass may potentially support chemotherapy election. Additionally, landmark evidence regarding the horizontal transfer of mitochondria to tumor-infiltrating lymphocytes offers a novel framework for understanding resistance to immunotherapy. While these preliminary results provide a promising roadmap for molecular stratification, their integration into routine practice remains a goal that requires further prospective validation in larger, multi-ethnic cohorts to ensure reproducibility and to distinguish functional drivers from passenger variants. Collectively, these emerging findings suggest that mtDNA analysis represents a valuable complementary approach to precision oncology in lung cancer.

Keywords:  Mitochondrial DNA; biomarkers; mtDNA copy number; mtDNA variants; non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105431
Mol Ther Oncol. 2026 Jun 18. 34(2): 201203

Engineering potent TILs from an immune-excluded tumor: Insights from chondrosarcoma.

Rusul Al-Marayaty, Seth M Pollack.

DOI: https://doi.org/10.1016/j.omton.2026.201203
Adv Sci (Weinh). 2026 Jun 15. e76143

Single-Cell RNA Editing Identifies T Cell ADAR1 as a Key Regulator of Immune Exhaustion and Anti-PD-1 Resistance in Colorectal Cancer.

Da Kang, Song-Zuo Xie, Yong-Zhou Luo, Xin-Pei Deng, Xi-Rong Tan, Ze-Geng Chen, Ling-Xing Zeng, Gong Chen, Pei-Rong Ding, Zhi-Zhong Pan, Rong-Xin Zhang.

  ADAR1-mediated RNA editing has been implicated in tumor immune evasion, primarily through tumor-intrinsic interferon (IFN) signaling. However, its cell-type-specific roles within immune compartments, particularly T cells, remain unclear in colorectal cancer (CRC). RNA editing landscapes were profiled using bulk RNA sequencing and full-length single-cell RNA sequencing. ADAR1 expression and RNA editing activity were analyzed across the tumor microenvironment (TME), followed by functional validation and multi-cohort clinical evaluation. Single-cell analyses revealed elevated ADAR1 activity in tumor-infiltrating T cells, defining an exhausted and proliferative T cell state associated with immune dysfunction. Functional experiments demonstrated that ADAR1 promotes T-cell exhaustion and impairs cytotoxic activity. In vivo adoptive transfer models further confirmed that ADAR1 overexpression in T cells limits antitumor efficacy. Mechanistically, ADAR1 activated the TGF-β-SMAD signaling pathway. Clinically, elevated ADAR1 expression in T cells was associated with reduced response to anti-PD-1 therapy across immunotherapy cohorts. These findings identify ADAR1 as a key regulator of dysfunctional T cell states in CRC and suggest that targeting ADAR1 activity in T cells may represent a promising strategy for improving immunotherapy efficacy and developing predictive biomarkers.

Keywords:  ADAR1; T cell exhaustion; TGF‐β signaling pathway; colorectal cancer; immunotherapy

DOI:  https://doi.org/10.1002/advs.76143
Am J Respir Cell Mol Biol. 2026 Jun 19. pii: aanag129. [Epub ahead of print]

Bridging the Gap: The Emerging Role of memory CD8+ T Cells in Fibrotic Interstitial Lung Disease.

Sherly I Celada, Stefan W Ryter, Robert P Baughman, Luc Van Kaer, Lindsay J Celada.

Interstitial lung disease (ILD) disproportionately affects older adults, yet the contribution of immunosenescence to disease pathogenesis remains poorly understood. In fibrotic ILDs (fILDs), CD8 + T cells accumulate in fibrotic regions, where they may drive disease by promoting cytotoxic inflammation, impairing epithelial repair, and sustaining senescence. CD8 + T cell exhaustion (CD8 + Tex) has also emerged as a hallmark of chronic lung disease, although its relationship to immunosenescence in ILD remains unclear. Here, we highlight the heterogeneity among CD8 + T cells in fILD, including effector- and senescent-like subsets, and identify programmed death (PD)-1 as a protective "brake" limiting tissue-damaging immunopathology. Functional profiling indicates that CD8 + T cells in fILD exhibit features consistent with ex-tissue-resident and effector memory CD8 + T cell subsets. Recent evidence from severe and post-acute viral injury demonstrates that PD-1hiCD8 + T cells balance protective immunity with restraint of fibrotic sequelae while also driving maladaptive epithelial remodeling through expansion of dysplastic basal-like cells and impaired alveolar regeneration. These observations suggest that CD8 + T cells in fILD may directly regulate the balance between tissue repair and fibrosis. Our recent studies have shown that the antifibrotic effects of pirfenidone and nintedanib may arise from selective modulation of profibrotic programs in CD8+/CD4 + T cells, lymphoid endothelial cells and dendritic cells. Collectively, these findings support a paradigm shift in which fILD reflects a dysregulation of local immune networks rather an inevitable consequence of aging. Most importantly, these networks are modifiable, offering opportunities for early detection, patient stratification, and stage-specific immunomodulatory interventions, with maladaptive memory CD8 + T cell functional states serving as potential biomarkers of disease susceptibility.

DOI: https://doi.org/10.1093/ajrcmb/aanag129
Cell Mol Life Sci. 2026 Jun 16.

Ovarian localization drives IL-7R-dependent CD8 coreceptor expression in peripheral double-negative T cells.

Toni Martin, Howard A Young, Enitome E Bafor.

  The ovary is an immunologically dynamic tissue that coordinates recurrent inflammation-like remodeling while preserving local T cell tolerance, yet whether it actively instructs infiltrating lymphocyte phenotype or passively enriches pre-existing subsets has not been directly tested. To address this, we used peripheral double-negative T cells (DNTs; CD3+CD4-CD8-NK1.1-) as a coreceptor-null system to detect tissue-imposed phenotypic change after ovarian entry. Using adoptive transfer, labeled splenic DNTs accumulated in the ovary relative to other tissue sites, and donor DNTs acquired surface CD8 expression within 4 days of ovarian localization. Dissociated ovarian cells were sufficient to drive CD8 upregulation on sorted DNTs in vitro, supporting that ovarian cellular cues can promote this response. Ovarian single-cell RNA-seq provided supportive evidence for Il7-expressing stromal subsets, and an Il7r-enriched DNT-associated lymphoid population, findings compatible with local IL-7-associated microenvironmental cues that may contribute to conditioning infiltrating T cells. Functionally, IL-7R was required for efficient CD8 upregulation after ovarian localization, and IL-7R or IL-7 deficiency shifted the endogenous ovarian DNT: CD8+ T cell balance. These findings support the ovary as an immune-conditioning environment in which tissue entry is associated with CD8 coreceptor induction on peripheral DNTs, and identify IL-7R signaling as a requirement for efficient induction in this setting.

Keywords:  Immune homeostasis; Lymphocyte adaptation; Ovarian immunity; Reproductive immunology; T cell plasticity; Tissue conditioning

DOI:  https://doi.org/10.1007/s00018-026-06295-x
J Egypt Natl Canc Inst. 2026 Jun 17. pii: 35. [Epub ahead of print]38(1):

Programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) in multiple myeloma.

Shimaa El-Garf, Reham Hammad, Eman Kandeel, Ahmed Rabea, Mona Alrayes.

   BACKGROUND: The bone marrow microenvironment in multiple myeloma (MM) is characterized by complex immune dysregulation involving multiple inhibitory pathways. Among these, the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis contributes to T-cell dysfunction; However, its isolated role within this multifactorial network remains incompletely defined.
METHODS: This prospective observational study performed a cross-sectional immunophenotypic analysis of 39 newly diagnosed MM (NDMM) patients. PD-1 expression on T cells and PD-L1 expression on bone marrow (BM) plasma cells (PCs) were assessed using flow cytometry. Associations with clinical and laboratory parameters were analyzed using correlation analysis.
RESULTS: PD-L1 mean fluorescence intensity (MFI) on PCs showed a positive correlation with BM T-cell percentage (r = 0.350, p = 0.029). PD-1 MFI on T cells correlated with total leukocytic count (TLC) (r = 0.326, p = 0.043). In International Staging System (ISS) stage III patients, PD-L1 expression on PC correlated with T cells% (r = 0.501, p = 0.018) and TLC (r = 0.427, p = 0.047), while PD-1 expression showed a strong positive correlation with TLC (r = 0.676, p = 0.001) and a negative correlation with age (r = - 0.492, p = 0.020). No significant association was observed with treatment response.
CONCLUSION: These findings provide an exploratory description of PD-1/PD-L1 expression patterns within the BM microenvironment in MM. Only in advanced cases according to ISS, PD-L1 expression on PC was linked to BM T cells frequency. PD-1/PD-L1 expression patterns were not linked to treatment response.

Keywords:  Immune checkpoints; Multiple myeloma; PD-1; PD-L1

DOI:  https://doi.org/10.1186/s43046-026-00379-2
Clin Transl Radiat Oncol. 2026 Jul;59 101212

Clinical efficacy of anti-PD-1 immunotherapy with localized non-ablative irradiation against metastatic lymph node in patients with metastatic gastric cancer.

Kosaku Mimura, Yoshiyuki Suzuki, Shotaro Nakajima, Takashi Ogata, Michael Fehlings, Katsuharu Saito, Yuya Yoshimoto, Daisaku Yoshida, Nozomu Machida, Takanobu Yamada, Hiroyuki Katoh, Hiroyuki Hanayama, Alessandra Nardin, Zenichiro Saze, Fumiaki Takahashi, Takashi Oshima, Koji Kono.

   Background: Cancer immunotherapy combining radiotherapy and anti-PD-1 therapy is a promising treatment strategy. However, the optimal method of radiotherapy to combine with anti-PD-1 therapy has not yet been established. We investigated the clinical efficacy of combinatorial immunotherapy with nivolumab and localized non-ablative irradiation against metastatic lymph node (Nivo-lRT_mLN) in patients with metastatic gastric cancer (m-GC).
Materials and Methods: This exploratory study included 16 patients with m-GC and nivolumab was administered after non-ablative irradiation, 22.5 Gy/5fractions, on one metastatic lymph node measuring 2.0 cm or larger. We evaluated the immunological characteristics associated with the therapeutic efficacy of Nivo-lRT_mLN by multiplex analysis of cytokines, T cell receptor repertoire and flow cytometric analysis using peripheral blood samples.
Results: More than 80% (13 out of 16) of patients had more than 5 metastases and 75% (12 out of 16) of patients had metastases in more than 2 organs. Rate of complete response (CR), partial response (PR), and stable disease (SD) in Nivo-lRT_mLN were 18.7%, 18.7%, and 25.0%. Median survival time was 10.3 months and 4 patients survived for more than five years without recurrence. Before treatment, IL-1ra level was significantly lower and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells was significantly higher in non-progressors (CR/PR/SD) compared to progressors (PD/NE) and the high group with frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells had significantly better overall survival (OS) than the low group (p = 0.0081). The time-dependent ROC AUC at both the level of IL-1ra and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells significantly predict OS (p = 0.0193 and p = 0.0442).
Conclusions: These preliminary findings indicated that localized non-ablative irradiation against metastatic lymph node has a potential to enhance the clinical efficacy of anti-PD-1 immunotherapy in patients with m-GC, and IL-1ra level and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells in peripheral blood before treatment may be candidate biomarkers to predict clinical efficacy of Nivo-lRT_mLN.

Keywords:  Gastric cancer; Metastatic lymph node; Nivolumab; Radioimmunotherapy

DOI:  https://doi.org/10.1016/j.ctro.2026.101212
Adv Sci (Weinh). 2026 Jun 19. e76082

Single-Cell Reveal GALNT7-Dependent Ferroptosis Suppression as a Mechanism of Immunotherapy Resistance in Non-Small Cell Lung Cancer.

Jiadi Gan, Qian Zheng, Deng Liu, Ruichao Nie, Menglin Yao, Xiaolong Tang, Renjie Xu, Jinghong Xian, Wenjun Meng, Wenxin Luo, Dan Liu, Guiyi Ji.

  Immunotherapy has transformed the treatment of non-small cell lung cancer (NSCLC), yet most patients fail to respond due to poorly understood resistance mechanisms. Here, integrative multi-omics analysis combining single-cell RNA-sequencing, bulk RNA-seq, and spatial transcriptomics is performed on tumors from NSCLC patients receiving immune checkpoint blockade (ICB). Transcriptomic profiling revealed that GALNT7, a glycosyltransferase, is selectively upregulated in non-responders (NR) and enriched in malignant epithelial cells. Functional and pathway analyses linked GALNT7 expression to suppression of ferroptosis-related signaling, whereas ICB responders (R) exhibited higher ferroptosis activity. Silencing GALNT7 in NSCLC cells impaired proliferation, induced apoptosis, and triggered ferroptotic cell death, characterized by lipid peroxidation and mitochondrial damage. Mechanistically, GALNT7 loss decreased SLC7A11 and GPX4, while upregulating the ferroptosis activator ACSL4. In vivo, GALNT7 knockdown reduced tumor growth, enhanced CD8+ T cell infiltration, and increased interferon gamma (IFN-γ) production within the tumor microenvironment. Moreover, combining GALNT7 depletion with PD-1 blockade achieved synergistic tumor suppression, which is reversed by Ferrostatin-1, indicating ferroptosis-dependent immunostimulation. Collectively, these findings uncover GALNT7 as a critical regulator linking ferroptosis and anti-tumor immunity, providing a mechanistic basis for ferroptosis-based sensitization to ICB therapy in NSCLC.

Keywords:  cancer research; cd8; gene knockdown; gene silencing; immune checkpoint; immunogenic cell death; immunotherapy; interferon gamma; t cell; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.76082
Surg Endosc. 2026 Jun 17.

Can combined biochemical and radiological responses enhance prognostic assessment after neoadjuvant therapy for locally advanced gastric cancer? A multicenter real-world study.

Hua-Long Zheng, Gang Wang, Bao-Long Li, Ling-Kang Zhang, Yu-Qin Sun, Yong-Hong Wang, Ju Wu, Shi-Chao Wu, Wei Zhao, Jun-Hua Yu, Ji-Yun Zhu, Hong-Hong Zheng, Cai-Ming Weng, Jian-Xian Lin, Ji-Ao Tang, Jia-Bin Wang, Chang-Ming Huang.

   BACKGROUND: Neoadjuvant chemotherapy for gastric cancer is assessed by RECIST but overlooks microscopic changes; incorporating CEA dynamics may improve evaluation accuracy.
METHODS: Retrospective analysis of 600 locally advanced gastric cancer (LAGC) patients (training:457; validation:143) from nine tertiary hospitals. The Biochemical and Radiologic Response System (BRRS) integrated RECIST 1.1-stratified radiological responses and peri-NAT carcinoembryonic antigen (CEA) dynamics. Predictive performance was evaluated using receiver operating characteristic (ROC) curves(AUC), time-dependent ROC, Akaike(AIC) and Bayesian(BIC) information criteria.
RESULTS: The BRRS was developed through Kaplan-Meier analysis of biochemical/radiologic responses to NACT, classifying 457 training-cohort patients into dual (DR, n = 168), single (SR, n = 185), and no responders (NR, n = 104).Three-year overall survival (OS) rates were 74.4% (DR), 60.6% (SR), and 35.0% (NR) (all P < 0.001). ypTNM 3-year OS rates were 96.4% (stage 0), 82.1% (stage I), 72.7% (stage II), 42.5% (stage III) (I vs. 0: P = 0.405; II vs. I: P = 0.122; III vs. II: P < 0.001), and tumor regression grade(TRG) 3-year OS rates were 93.6, 74.1, 45.9, 46.7% (TRG1 vs. 0:P = 0.060; TRG2 vs. 1:P = 0.001; TRG3 vs. 2:P = 0.583). BRRS (AUC = 0.708, AIC = 992.57, BIC = 995.20) outperformed ypTNM (AUC = 0.678, AIC = 1007.18, BIC = 1008.81) and TRG (AUC = 0.661, AIC = 1012.03, BIC = 1015.65) in OS prediction. Adjuvant chemotherapy improved OS/disease-free survival (DFS) in SR (OS:62.9 vs. 41.4%, P = 0.041; DFS:55.7 vs. 31.6%, P = 0.020) and NR groups (OS:39.1 vs. 16.7%, P = 0.030; DFS: 36.1 vs. 11.9%, P = 0.019) but not in DR (OS: 75.4 vs. 66.7%, P = 0.765; DFS: 66.7 vs. 71.4%, P = 0.455). The results from the validation cohort were consistent.
CONCLUSION: BRRS outperformed conventional ypTNM and TRG systems in prognostication. Postoperative chemotherapy may be omitted in DR patients.

Keywords:  CEA; Gastric cancer; Neoadjuvant chemotherapy; Prognosis; RECIST

DOI:  https://doi.org/10.1007/s00464-026-12858-7
Front Immunol. 2026 ;17 1818138

Tumor immune microenvironment states inferred from TLS-associated immune-cell composition stratify prognosis in hepatocellular carcinoma.

Chihyuan Cheng, Geng Chen, Jing Zhang, Liman Qiu, Zhenli Li, Xiuqing Dong, Chenfan Lu, Qiming Wu, Xiaohui Peng, Zhixiong Cai, Yongyi Zeng.

   Background: Tertiary lymphoid structures (TLS) are ectopic immune hubs in the tumor immune microenvironment (TIME) associated with prognosis and immunotherapy response, yet commonly used TLS structural descriptors show inconsistent associations with prognosis in hepatocellular carcinoma (HCC). Here, we propose a TLS-associated immune-cell composition framework that quantifies the TIME state and predicts patient outcomes.
Methods: By integrating an HCC single-cell atlas with literature-curated TLS gene sets, we defined six TLS-associated immune components (TLS6). Using TLS6 as a reference, we applied BayesPrism deconvolution to infer the relative abundance of TLS6 from bulk tumor transcriptomes. Given the divergent prognostic associations across TLS6 fractions, we applied LASSO-Cox regression to derive a two-feature TLS RiskScore retaining regulatory T cells and cDC2 cells.
Results: The TLS RiskScore stratified overall survival in TCGA-LIHC and ICGC LIRI-JP and was associated with response to PD-1 blockade in an independent anti-PD-1-treated HCC cohort. In multicenter FFPE tissues, a multiplex immunofluorescence (mIF) implementation quantifying TLS-localized CD4+FOXP3+ regulatory T cells and CD11c+CD1c+ cDC2 cells reproduced prognostic stratification without model refitting.
Conclusions: Collectively, these results support a compact, translatable TLS-associated immune-cell composition framework that provides a computable TIME-state measure associated with prognosis and response to PD-1 blockade in HCC.

Keywords:  hepatocellular carcinoma; immune-cell composition; immunotherapy response; tertiary lymphoid structures; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1818138
Cell Rep Med. 2026 Jun 16. pii: S2666-3791(26)00293-4. [Epub ahead of print] 102876

TIGIT-targeted IL-12 fusion protein engages NK and CD8+ T cells for potent tumor immunotherapy.

Maoxing Tang, Yingying Huang, Jiacheng Bi, Dandan Meng, Xiaodong Zheng, Hui Peng, Rui Sun, Hongdi Ma, Zhigang Tian, Haoyu Sun, Xiaohu Zheng.

  The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named αTIGIT-IL12 (T-12), which fuses the 13G6 (αTIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8+ T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8+ T cells. T-12 preferentially activates tumor-infiltrating NK and CD8+ T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.

Keywords:  CD8(+)T cells; IL-12; NK cells; TIGIT; cancer immunotherapy; immunocytokine

DOI:  https://doi.org/10.1016/j.xcrm.2026.102876
Front Immunol. 2026 ;17 1871148

Mitochondrial transfer in the tumor microenvironment: a dynamic determinant of cancer plasticity, immune dysfunction, and therapeutic opportunity.

Zhenyuan Xu, Qingli Zhou, Jifei Miao.

  Intercellular mitochondrial transfer has emerged as a significant mode of communication within the tumor microenvironment (TME). We propose that this process operates as a stress-adaptive organelle economy, redistributing three biologically decisive assets (respiratory competence, redox tolerance, and stress history) among tumor, immune, and stromal cells according to local metabolic asymmetry. Cancer cells acquire healthy mitochondria from stromal and immune populations, thereby restoring oxidative phosphorylation, expanding metabolic plasticity, and driving chemoresistance. Tumor cells also engage in outward transfer that is recipient-selective. Damaged mitochondria may be exported to CD8+ T cells and fibroblasts, corrupting effector function and reprogramming the stroma, whereas functional mitochondria may be delivered to pro-tumor immune populations such as M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells to sustain their immunosuppressive activity. Functional mitochondria therefore play a dual role in tumorigenesis. The consequences for antitumor immunity depend on donor identity, cargo quality, and recipient lineage rather than on transfer itself. The principal transport routes are tunneling nanotubes, extracellular vesicles, and cell fusion, but biological outcome is ultimately governed by a post-transfer fate checkpoint involving PINK1/Parkin-mediated mitophagy and USP30-facilitated retention. Therapeutically, the goal is not to block or enhance transfer globally but to achieve context-selective modulation within an inherently bidirectional system.

Keywords:  cancer plasticity; extracellular vesicles; mitochondrial transfer; t cell exhaustion; tumor microenvironment; tunneling nanotubes

DOI:  https://doi.org/10.3389/fimmu.2026.1871148
Front Immunol. 2026 ;17 1860442

Chemical priming potentiates mesothelin-targeting chimeric antigen receptor-engineered NK-92 antitumor activity by improving tumor trafficking and cytotoxic killing dynamics.

Ki Seo Ryu, Hail Park, Eunchong Maeng, Jun-Yeon Lim, Duck Cho, Seung Hee Choi, Kyung-Soon Park.

   Introduction: Chimeric antigen receptor-engineered natural killer (CAR-NK) cells have emerged as a promising strategy for cancer immunotherapy; however, their efficacy against solid tumors remains limited by inefficient tumor trafficking and impaired cytotoxic function within the tumor microenvironment. Here, we investigated whether a non-genetic chemical priming strategy could pre-arm CAR-NK cells and enhance their migratory and cytotoxic functions.
Methods: Based on our previous findings that transient exposure to 25 kDa branched polyethylenimine (25KbPEI) induces a primed phenotype, mesothelin-targeting CAR-NK-92 cells were chemically primed and evaluated for migration, cytotoxicity, killing dynamics, perforin accumulation, cytokine production, and in vivo antitumor efficacy in a SKOV3 xenograft model.
Results: Chemical priming significantly enhanced cytotoxicity and degranulation against ovarian cancer cells without compromising cell viability. Primed CAR-NK cells showed increased CCR7 expression and improved tumor-directed migration. Live-cell imaging further revealed accelerated target engagement and shortened killing time, indicating enhanced cytotoxic kinetics. In addition, chemical priming increased perforin accumulation and IFN-γ production. In the SKOV3 xenograft model, primed CAR-NK cells achieved superior tumor control and increased intratumoral infiltration compared with non-primed CAR-NK cells, while maintaining a favorable safety profile.
Discussion: Collectively, these findings demonstrate that chemical priming enhances CAR-NK cell function and provides a promising non-genetic strategy to improve CAR-NK cell activity against solid tumor models.

Keywords:  25 kDa branched polyethylenimine; chemical priming; chimeric antigen receptor-engineered natural killer cells; mesothelin; ovarian cancer; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2026.1860442
Research (Wash D C). 2026 ;9 1310

Rejuvenated Hematopoietic Stem and Progenitor Cell-Engineered CAR-Armored Natural Killer T Cells for Malignant Pleural Mesothelioma.

Yan-Ruide Li, Yichen Zhu, Zhe Li, Xinyuan Shen, Shuo Li, Yuning Chen, Zibai Lyu, Jie Huang, Nathan Y Ma, Catherine Zhang, Annabel S Zhao, Yanxin Tian, Xianghong Jasmine Zhou, Lili Yang.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy arising from the pleural lining, characterized by a dismal prognosis and limited therapeutic options. Mesothelin (MSLN)-directed chimeric antigen receptor (CAR)-armored T (CAR-T) cell therapies have shown encouraging preliminary outcomes; however, autologous manufacturing approaches remain constrained by logistical complexity and prolonged production timelines, which are suboptimal for patients with rapidly advancing disease. Here, we describe the development of human allogeneic interleukin-15-augmented, MSLN-specific, CAR-armored invariant natural killer T (Allo15MCAR-NKT) cells. These cells are generated through genetic modification of hematopoietic stem and progenitor cells, followed by a clinically guided CAR-NKT cell differentiation, maturation, and expansion process. This approach supports scalable production with high cellular yield, purity, and translational feasibility. Functionally, Allo15MCAR-NKT cells exhibit robust antitumor efficacy in vitro and demonstrate robust therapeutic activity across multiple in vivo MPM xenograft models, including subcutaneous and lung metastasis models. In addition, they actively modulate the tumor microenvironment by targeting CD1d+ tumor-associated macrophages. Phenotypic analysis reveals a rejuvenated cellular profile, marked by low expression of exhaustion-associated and inhibitory receptors, including PD-1, TIM-3, LAG-3, CTLA-4, and TIGIT, consistent with sustained functional capacity. Importantly, these cells display a favorable safety profile, with minimal evidence of graft-versus-host disease, cytokine release syndrome, brain infiltration or neurotoxicity, and no detectable off-tumor effects. Collectively, these findings support the development of a clinically translatable, off-the-shelf CAR-NKT cell therapy for the treatment of MPM.

DOI: https://doi.org/10.34133/research.1310
Transl Oncol. 2026 Jun 19. pii: S1936-5233(26)00207-X. [Epub ahead of print]71 102870

A spatial immune scoring system based on the tumor microenvironment features improves prognostic stratification in lung adenocarcinoma.

Wei Luo, Jia Jia, Qi Wang, Xiaoqing Li, Fang Yang, Yongtian Zhao, Zilu Li, Lin Li, Xiaodan Wang, Mingyao Meng, Haiyan Guo, Wanli Zheng, Liqiong Wang, Dingbiao Li, Zongliu Hou, Yangfan Guo.

  The spatial heterogeneity of the tumor immune microenvironment (TME) in lung adenocarcinoma (LUAD) limits the prognostic accuracy of traditional TNM staging. Moreover, conventional T cell based immune scores established for other solid tumors fail to effectively stratify patient outcomes in LUAD. To address this, we applied quantitative multiplex immunofluorescence to map the spatial immune contexture of LUAD and developed the Lung Cancer Immune Score (LCIS). This framework integrates four key biomarkers: CD68⁺HLA-DR⁺ macrophages, CD20⁺ B cells, PD-1⁺ cells and Ki67⁺ proliferating tumor cells, to quantify the balance between tumor proliferation and host anti-tumor immunity across the tumor core and invasive margin. High LCIS scores independently predicted improved overall survival in both the discovery (p = 0.02) and independent validation (p = 0.017) cohorts, outperforming conventional clinical parameters and single biomarkers. Specifically, LCIS effectively sub-stratified patients with Stage II and III LUAD into refined prognostic groups, resolving the prognostic ambiguity within the same TNM stage. Overall, by quantifying the interaction between tumor proliferation and antigen-directed immune activation, the LCIS serves as a spatial biomarker to refine prognosis and inform personalized therapy in LUAD.

Keywords:  Immune scoring system; Lung adenocarcinoma; Prognostic stratification; Spatial profiling; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.tranon.2026.102870