bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2026–08–16
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Correlation of tumor-infiltrating lymphocyte spatial distribution patterns with HER2 expression status and prognostic significance in gastric adenocarcinoma: a retrospective study based on digital pathology.
  2. Thin Nevus-Associated Melanoma: Beyond MIA Score Risk Stratification.
  3. BCL11B targeting in tumor CD8 + T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity.
  4. TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in colorectal cancer.
  5. Prognostic value of tumor-infiltrating lymphocytes and their association with clinical and pathological factors in gastric cancer.
  6. TP53 Mutation and Tumor-Infiltrating Lymphocytes as Predictors of PD-1/PD-L1 Inhibitor Efficacy in PD-L1-High Advanced NSCLC.
  7. Immunohistochemistry-based molecular subtypes and stromal tumor-infiltrating lymphocytes in triple-negative breast cancer: a chemotherapy-only cohort.
  8. Simultaneous gene engineering of T cells with multiple neoantigen-specific T cell receptors for adoptive cell transfer.
  9. A radiomic approach to non-invasively decode tumor immune microenvironmental features in surgically resected non-small cell lung cancer.
  10. Rethinking lymphodepleting preconditioning in adoptive T cell therapy for durable tumor control.
  11. mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.
  12. Menaquinone-4 protects CD8+ T cells from ferroptosis to enhance anti-tumor immunity.
  13. DLL3 serves as a pivotal hub bridging malignant progression and immunosuppression in NECC with therapeutic implications validated via the organoid-TIL co-culture system.
  14. Mechanistic roles and clinical applications of tertiary lymphoid structures in colorectal cancer drug resistance.
  1. Am J Cancer Res. 2026 ;16(7): 2937-2954
    Correlation of tumor-infiltrating lymphocyte spatial distribution patterns with HER2 expression status and prognostic significance in gastric adenocarcinoma: a retrospective study based on digital pathology.
    Xinwu Mao, Shangwei Zhong, Xiaowen Zhang, Yuting Liu, Luqing Zhou.
       BACKGROUND: The spatial distribution of tumor-infiltrating lymphocytes (TILs) has prognostic value in solid tumors, but its relationship with HER2 status in gastric adenocarcinoma remains poorly characterized.
    METHODS: TIL densities in the tumor center (CT) and at the invasive margin (IM) were assessed on H&E-stained slides using QuPath, and the edge/center ratio (E/C ratio = IM-TILs/CT-TILs) was calculated. The optimal cut-off for E/C ratio was determined by maximizing the log-rank statistic. Survival analyses were performed using Kaplan-Meier and Cox regression.
    RESULTS: The HER2-positive group (n = 35) exhibited significantly lower CT-TILs (11.92% vs. 20.98%, P < 0.001) and a higher E/C ratio (2.11 vs. 1.25, P < 0.001) than the HER2-negative group (n = 165). Using an optimal cut-off of 1.57, high E/C ratio was associated with significantly worse overall survival (OS) in the whole cohort (median 14.64 vs. 42.87 months; log-rank P < 0.001). Multivariate Cox regression, adjusting for clinicopathological factors, revealed that the E/C ratio as a continuous variable was independently prognostic (HR = 1.398, P < 0.001), and a significant interaction between HER2 status and E/C ratio was observed (HR = 1.844, P = 0.001). Dichotomization at E/C > 1.57 provides significant prognostic stratification, an effect that is modified by HER2 status; however, due to the small HER2-positive subgroup, these findings require validation in larger independent cohorts.
    CONCLUSIONS: HER2-positive gastric adenocarcinoma exhibits an "edge-limiting" immune phenotype with elevated E/C ratio. Digital assessment of TILs on routine H&E sections is simple and promising for clinical translation.
    Keywords:  Gastric adenocarcinoma; HER2; digital pathology; prognosis; spatial distribution; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.62347/PEJP1288
  2. Cancers (Basel). 2026 Jul 30. pii: 2456. [Epub ahead of print]18(15):
    Thin Nevus-Associated Melanoma: Beyond MIA Score Risk Stratification.
    Federico Venturi, Maria Luisa Orlando, Barbara Corti, Paola Valeria Marchese, Francesca Comito, Barbara Melotti, Elisabetta Magnaterra, Biagio Scotti, Aurora Maria Alessandrini, Leonardo Veneziano, Elena Maria Cama, Emi Dika.
      Background: Nevus-associated melanomas (NAM) are frequently diagnosed at an early stage, yet risk heterogeneity within thin tumors remains poorly characterized. Whether classical histopathologic features can refine risk stratification in this subgroup is unclear. Objective: To evaluate the prognostic significance of histopathologic features, particularly mitotic activity and tumor-infiltrating lymphocytes (TILs), in thin nevus-associated melanoma (pTis-pT1a) (<0.8 mm). Methods: Retrospective cohort study of 138 consecutive patients with histologically confirmed NAM diagnosed at a tertiary dermatologic oncology center (October 2006-December 2023). Staging was reassessed as per AJCC 8th edition. A predefined subgroup analysis of 100 patients with thin NAM (pTis-pT1a) evaluated adverse outcomes (distant metastasis or death) within 10 years. Associations were assessed using χ2 tests and logistic regression. Results: Median age was 53.5 years (IQR 44.0-63.8); 60.9% were male. Median Breslow thickness was 0.57 mm (IQR 0.4-0.8). Overall survival was 90.9% at 5 years and 86.0% at 10 years. Among thin NAM, eight patients (8%) experienced adverse outcomes. Mitotic activity ≥ 1/mm2 was associated with higher adverse event rates (10.9% vs. 2.8%; OR, 4.30; 95% CI, 0.51-36.43; p = 0.18). A gradient was observed across TIL categories: adverse events occurred in 13.8% with absent TILs, 7.3% with non-brisk, and 0% with brisk TILs (p = 0.24). Exploratory multivariable analysis showed consistent effect directions without reaching statistical significance. Conclusions: Thin nevus-associated melanomas are not uniformly low risk. Mitotic activity and absent TILs were associated with higher adverse event rates, suggesting that classical histopathologic features may refine risk stratification in early-stage NAM.
    Keywords:  early-stage melanoma; mitotic rate; nevus-associated melanoma; risk stratification; thin melanoma; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/cancers18152456
  3. bioRxiv. 2026 Aug 07. pii: 2026.08.03.742578. [Epub ahead of print]
    BCL11B targeting in tumor CD8 + T cells amplifies anti-tumor response by blocking exhaustion while promoting stemness and cytotoxicity.
    Leonardo Silvane, Tomas Zelenka, Divya P Talada, Valeriu B Cismasiu, Shamima Islam, Raghwendra P Singh, Zefanias Ngove, Sayan Chakraborty, MacLean S Hall, Jamie L Blauvelt, Erika Eksioglu, Soraya Zorro Manrique, Joseph O Johnson, Alyssa N Obermayer, Alex Alfaro, Wen Huang, Amod Sarnaik, Ahmad A Tarhini, John E Mullinax, Erin George, Patrick Hwu, Eduardo Davila, Jose R Conejo-Garcia, Yenan T Bryceson, Dung-Tsa Chen, Timothy I Shaw, Shari Pilon-Thomas, Dorina Avram.
      Tumor infiltrating CD8 + T cells (TILs) progress to a state of terminal exhaustion (Ttex) which have impaired functionality and are nonrenewable. However their precursors (Tpex) are renewable and can generate efficient effector cells. We started from the observation that melanoma patients undergoing therapy with checkpoint inhibitors show increased survival when their T cells have low BCL11B mRNA. In line with this, ablation of Bcl11b in CD8 + TILs conferred a superior anti-tumor response in murine melanoma and ovarian cancer models. Bcl11b KO TILs failed to progress to the Ttex state and retained elevated stemness. Bcl11b exerted its role by repressing expression of essential transcription factors (TF) controlling stemness, and conversely by promoting expression of exhaustion-associated TFs and inhibitory receptor genes, through complex epigenetic control. In addition, Bcl11b KO CD8 + T cells showed increased Ag-specific cytolytic activity and elevated Gzmb and Prf1 proteins, but no increase in their mRNAs, however presented higher expression of genes with role in translation. Furthermore, CRISPR-CAS9-mediated deletion of BCL11B in human TILs from a patient with poor response to adoptive cell therapy with autologous TILs, improved their cytolytic activity and promoted expression of the stemness-associated TF TCF1, underlying its potential therapeutic use.
    HIGHLIGHTS: Adoptive transfer of Bcl11b KO CD8 + TILs surpasses WT in tumor burden reduction Bcl11b ablation reprograms TILs and impairs the progression to Ttex state Bcl11b KO CD8 + T cells have elevated cytotoxicity and kill only Ag-MHCI targets BCL11B deletion in nonresponder ACT-TIL improves cytolytic activity and elevates TCF1.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.08.03.742578
  4. Mol Ther Oncol. 2026 Sep 17. 34(3): 201294
    TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in colorectal cancer.
    Audrey Merienne, Kathleen Ducoin, Cécile Deleine, Mathilde Deiber, Margot Machu, Edouard Leveque, Romain Oger, Emilie Duchalais, Pierre Fourquier, Céline Bossard, Nathalie Labarrière, Houssem Benlalam, Anne Jarry, Nadine Gervois-Segain.
      Loss of components of the antigen processing machinery, such as the transporter associated with antigen processing 1 (TAP1), is a frequent immune escape mechanism in colorectal cancer (CRC). Although TAP1 deficiency impairs classical antigen presentation, it may also generate alternative T cell epitopes associated with impaired peptide processing (TEIPP) exploitable for immunotherapy. We investigated whether human CRC harbors functional CD8 T cells targeting TAP1-deficient tumor cells. TAP1 expression was analyzed by immunohistochemistry in tumors from 193 CRC patients (156 microsatellite-stable [MSS] and 37 microsatellite-instable [MSI]). CD8 tumor-infiltrating lymphocytes (TILs) were expanded from 61 CRC samples and tested for reactivity against a TAP1-deficient CRC cell line. 26% of CRC tumors displayed reduced or absent TAP1 expression, with no significant association with overall survival. CD8 TILs reactive to TAP1-deficient tumor cells were detected in 46% of patients and their frequency correlated with low TAP1 expression, particularly in MSI CRCs. A CD8 T cell clone selectively recognized and efficiently killed TAP1-deficient CRC cells in an HLA-B∗07:02-restricted manner, inducing robust tumor cell apoptosis in both 2D cultures and 3D spheroid models. These findings demonstrate that TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in CRC, supporting the development of immunotherapies directed against TAP1-deficient tumors.
    Keywords:  2D-3D co-culture models; CD8 T cell response; TAP1 deficiency; TILs; colorectal cancer
    DOI:  https://doi.org/10.1016/j.omton.2026.201294
  5. Arq Bras Cir Dig. 2026 ;pii: S0102-67202026000100609. [Epub ahead of print]39 e1948
    Prognostic value of tumor-infiltrating lymphocytes and their association with clinical and pathological factors in gastric cancer.
    Dhouha Bacha, Ines Mallek, Mohamed Hajri, Amani Benzarti, Farah Loued, Sana Ben-Slama, Lassad Gharbi, Ahlem Lahmar.
       BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes has been studied in several cancers, but in gastric cancer, their evaluation by standard hematoxylin-eosin staining remains controversial.
    AIMS: To analyze the prognostic value of tumor-infiltrating lymphocytes in gastric cancer and to investigate the association between tumor-infiltrating lymphocyte levels and a range of clinical and pathological factors in gastric cancer.
    RESULTS: Forty-four patients were included with a mean age of 62 years, and 77% of the patients were classified as having pathological tumor stage 3 or pathological tumor stage 4. Lymph node metastases were noted in 66% of our patients. At diagnosis, 57% of patients were at an advanced stage (III). Patients with distant metastases were not included in this study. Evaluation of tumor-infiltrating lymphocytes in hematoxylin-eosin staining found that the mean tumor-infiltrating lymphocyte rate was 43 (extremes: 5-90%). 36% of patients had a tumor-infiltrating lymphocyte rate >50%. The overall survival of our patients was 40 months. Patients with tumor-infiltrating lymphocytes >50% had greater survival, without a significant correlation (p=0.275). A tumor-infiltrating lymphocyte rate =50% was correlated with age >50 years (p=0.030), presence of lymph node involvement (p=0.023), and advanced tumor stage (III+IV) (p=0.05). In a multivariate analysis, the presence of lymph node involvement (p=0.045) and advanced tumor stage (III+IV) (p=0.015) were identified as independent factors associated with a low tumor-infiltrating lymphocyte rate =50%.
    CONCLUSIONS: Poor prognostic factors for gastric cancer (age >50 years, presence of lymph node involvement, and advanced tumor stage) were associated with a low tumor-infiltrating lymphocyte rate assessed by hematoxylin-eosin staining. However, standardization of tumor-infiltrating lymphocyte assessment is essential to allow comparability between studies and integrate this parameter into routine practice.
    DOI:  https://doi.org/10.1590/0102-672020260000019e1948
  6. Cancer Rep (Hoboken). 2026 Aug;9(8): e70648
    TP53 Mutation and Tumor-Infiltrating Lymphocytes as Predictors of PD-1/PD-L1 Inhibitor Efficacy in PD-L1-High Advanced NSCLC.
    Hui Yan, Qian Xu, Yushuang Zheng, Meng Shen, Dapeng Li.
       BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is widely used to guide immune checkpoint inhibitor (ICI) therapy in advanced nonsmall cell lung cancer (NSCLC); however, substantial heterogeneity in clinical outcomes persists among patients with high PD-L1 expression. Reliable biomarkers for further stratifying this population are still lacking. This study investigated whether genomic alterations and features of the tumor immune microenvironment could explain this variability.
    METHODS: We conducted a retrospective single-center study including 91 patients with advanced NSCLC and PD-L1 tumor proportion score (TPS) ≥ 50% who received ICI-based therapy. Clinical outcomes were assessed according to PD-L1 expression levels, genomic profiles, and tumor immune microenvironment characteristics. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) were evaluated in available tumor specimens from 75 patients. Multiplex immunohistochemistry (mIHC) was performed in a subset of 30 patients to characterize the immune cellular composition underlying TIL-based stratification. Kaplan-Meier survival analysis and multivariable Cox regression were used to identify factors associated with progression-free survival (PFS) and overall survival (OS).
    RESULTS: At a median follow-up of 19.1 months, the objective response rate was 31.9%, the median PFS was 10.7 months, and the median OS was 43.5 months. No significant survival differences were observed between the TPS 50%-89% and TPS ≥ 90% subgroups. TP53 mutation was associated with shorter PFS and remained an independent adverse prognostic factor. In contrast, high TIL infiltration was independently associated with improved PFS and OS, and this OS benefit was most pronounced in the TPS ≥ 90% subgroup. mIHC analysis revealed that high-TIL tumors exhibited increased stromal CD8+ T-cell infiltration, enriched NK-cell populations, and a more proinflammatory macrophage profile, providing biological support for TIL-based stratification. TLS presence was not significantly associated with survival outcomes.
    CONCLUSIONS: PD-L1 expression alone does not fully account for the outcome heterogeneity observed in PD-L1-high NSCLC treated with ICIs. Integrating genomic alterations-particularly TP53 mutation status-with tumor immune microenvironment features, such as TIL density, may help refine prognostic stratification in this population.
    Keywords:  PD‐L1‐high expression; TP53 mutation; immune checkpoint inhibitors; nonsmall cell lung cancer (NSCLC); tumor‐infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.1002/cnr2.70648
  7. Oncologist. 2026 Aug 12. pii: oyag322. [Epub ahead of print]
    Immunohistochemistry-based molecular subtypes and stromal tumor-infiltrating lymphocytes in triple-negative breast cancer: a chemotherapy-only cohort.
    Jesus Edgardo Hernandez-Hernandez, Alejandro Mohar, César Octavio Lara-Torres, Daniela Vazquez-Juarez, Tamara Palacios, Lourdes Peña-Torres, Guadalupe Moncada-Claudio, Areli Velazquez-Martinez, Paula Cabrera-Galeana, Gabriela Sofía Gómez-Macías, Fany Iris Porras-Reyes, Víctor Manuel Pérez-Sánchez, Alejandro Aranda-Gutierrez, Cynthia Villarreal-Garza.
       BACKGROUND: Triple-negative breast cancer (TNBC) is a biologically heterogeneous, aggressive disease where immunohistochemistry (IHC)-based algorithms, defining luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immunosuppressed (BLIS), mesenchymal (MES), and unclassifiable (UC) subtypes, offer a pragmatic alternative to transcriptomics. This study evaluated clinical trajectories and survival outcomes associated with IHC-based molecular subtypes and stromal tumor-infiltrating lymphocytes (sTILs) across distinct subgroups.
    METHODS: A retrospective analysis of 289 women with TNBC treated with chemotherapy-only regimens analyzed molecular subtypes across four clinical groups: non-recurrent, recurrent, progression during neoadjuvant chemotherapy, and de novo metastatic disease. IHC-based subclassification included androgen receptor (AR), CD8, FOXC1, and DCLK1 biomarkers. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models.
    RESULTS: The cohort included non-recurrent (43.9%), recurrent (26.3%), neoadjuvant progressors (11.5%), and de novo stage IV (18.3%) cases. IM subtype (16.3%) was enriched in non-recurrent cases with the highest median sTILs levels (20.0%). BLIS (26.3%) and UC (39.4%) subtypes predominated in recurrent and metastatic disease, while MES subtype (9.0%) predominated in neoadjuvant chemotherapy progressors. In early-stage disease, sTILs ≥10% independently predicted superior OS (HR 0.63, 95% CI 0.40-1.0; p = 0.049), showing no prognostic role in the de novo stage IV group. Molecular subtypes lost independent significance in multivariable models.
    CONCLUSIONS: Clinicopathological factors and sTILs remain primary prognostic determinants in TNBC. Although IHC-based molecular subtypes were not independent survival predictors, their differential clinical distribution validates their biological relevance to identify therapeutic vulnerabilities, and to guide precision medicine and de-escalation strategies.
    Keywords:  immunohistochemistry; molecular subtypes; prognosis; stromal TILs; triple-negative breast cancer
    DOI:  https://doi.org/10.1093/oncolo/oyag322
  8. Mol Ther Adv. 2026 Sep 10. 34(3): 201810
    Simultaneous gene engineering of T cells with multiple neoantigen-specific T cell receptors for adoptive cell transfer.
    Melinda Magna, Lior Levy, Krisztian Csomos, Aaron J Dinerman, Abraham A Hakim, Noam Levin, Sanghyun P Kim, Nikolaos Zacharakis, Neilesh B Parikh, Brian D Bui, Aarushi Bhasin, Rachel K Beyer, Stephanie L Goff, Frank J Lowery, Steven A Rosenberg, Sri Krishna.
      T cell receptor (TCR) T cell therapy targeting tumor-specific antigens and neoantigens can mediate impressive tumor regressions in solid tumors. However, solid epithelial tumors are characterized by inherent tumor heterogeneity that can lead to tumor escape and thwart TCR T cell therapy. Targeting multiple cancer antigens in a single TCR T product may help overcome the antigen heterogeneity among metastatic deposits. However, the time and expense of preparing multiple TCR-transduced T cell populations under good manufacturing practice (GMP) for patient treatment has limited this approach to target 1 or 2 antigens. Here, we design strategies to enhance TCR T cell therapy efficacy by simultaneously targeting multiple neoantigens. We developed two novel manufacturing processes to introduce multiple neoantigen-specific TCRs into T cells, using gamma-retroviral delivery. These strategies resulted in multipotent neoantigen-reactive TCR T cell products, which demonstrated functionality against multiple tumor neoantigens and displayed cytotoxicity against heterogeneous tumor cells in vitro. High-dimensional single-cell and single-clone T cell analysis confirmed the presence of multiple TCR-expressing T cells in the products and demonstrated functional recognition of multiple neoantigens. This study, thus, addresses the challenges of tumor heterogeneity and immune escape mechanisms in solid tumors, paving the way for more effective TCR T cell therapies in cancer treatment.
    Keywords:  TCR T cell therapy; adoptive cell transfer; cancer; cell therapy manufacturing; engineered T cell; immunotherapy; mutated neoantigens; solid tumor
    DOI:  https://doi.org/10.1016/j.omta.2026.201810
  9. Tumori. 2026 Aug 12. 3008916261462796
    A radiomic approach to non-invasively decode tumor immune microenvironmental features in surgically resected non-small cell lung cancer.
    Giulia Mazzaschi, Maurizio Balbi, Ludovica Leo, Lucas Moron Dalla Tor, Roberto Rosati, Cristina Marrocchio, Rebecca Mura, Gianluca Milanese, Simona D'Agnelli, Giovanni Bocchialini, Monica Pluchino, Roberta Minari, Michela Verzè, Letizia Gnetti, Prisca Tamarozzi, Alessandra Dodi, Francesca Trentini, Stefano Bettati, Simonetta Croci, Luca Ampollini, Federico Quaini, Marcello Tiseo, Nicola Sverzellati.
       INTRODUCTION: This study aimed to develop radiomics-based multivariate classifiers able to non-invasively decipher the tumor immune microenvironment (TIME) in resected Non-small cell lung cancer (NSCLC) patients.
    METHODS: Tumor-infiltrating lymphocytes (TILs) subpopulations and PD-L1 TPS were immunohistochemically assessed. Radiomic features (RFs) were extracted from preoperative CT scans using the PyRadiomics platform. Six machine learning-based models were built to predict distinct TIME-related endpoints: PD-L1 (M1), CD8/CD3 ratio (M2), PD1/CD8 ratio (M3), CD3+ TILs (M4), CD4+ TILs (M5), CD8+ TILs (M6). Except for PD-L1 (classified as positive vs negative), patients were dichotomized into high versus low groups based on median values. Model development relied on Random Forest classifiers with sequential feature selection and internally validated through Leave-One-Out Cross-Validation splitsResults:A total of 98 patients with stage I-IIIA resected NSCLC were included. From 1702 initially extracted RFs per scan, 231 non-redundant features (116 tumor and 115 peritumoral) were retained after correlation filtering. Final models incorporated between 3 and 7 RFs derived from both tumor and peritumoral regions. Model performance showed accuracy, precision, sensitivity, receiver operating curve (ROC) Area under the Curve (AUC) and precision-recall curve (PRC) AUC values ranging from 70% to 80%, with slightly lower performance for M2. Specificity ranged from 55% to 77%, with the highest value observed in the CD8+ TILs model (M6). Feature selection varied across models, although one peritumoral feature (HLL-wavelet GLCM Correlation) was consistently selected in four models (M1, M2, M4, M5).
    CONCLUSIONS: Tumoral and peritumoral CT-based radiomics might effectively intercept TIME features, thus suggesting a potential non-invasive approach in resected NSCLC patients.
    Keywords:  NSCLC; machine learning; radiomics; tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.1177/03008916261462796
  10. Mol Ther Oncol. 2026 Sep 17. 34(3): 201293
    Rethinking lymphodepleting preconditioning in adoptive T cell therapy for durable tumor control.
    Diego Figueroa, Vincenzo Borgna, Alvaro Lladser.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201293
  11. Sci Rep. 2026 08 08. pii: 24539. [Epub ahead of print]16(1):
    mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.
    Janna Krueger, Janne J Ruotsalainen, Johannes Lutz, Regina Heidenreich.
      Adoptive T cell therapy (ACT) has shown remarkable clinical success in treating haematological malignancies; however, its efficacy against solid tumours remains limited. This is largely due to poor persistence and functionality of transferred T cells, restricted tumour infiltration, and the presence of an immunosuppressive tumour microenvironment. Here, using the MC38-OVA murine tumour model, we tested whether combining Transgenic T cell receptor (TCRtg) T cell therapy with an adjunctive mRNA-based immunotherapy could address these challenges and drive effective and long-lasting anti-tumour response. Tumour-bearing mice were treated with different numbers of in vivo-activated, ovalbumin (OVA)-specific TCRtg CD8+ T cells harvested from OT-I mice, either alone or in combination with lipid nanoparticle (LNP)-encapsulated mRNA encoding OVA. Tumour progression was monitored, and analyses were performed to assess survival, T cell expansion, phenotype, infiltration, and effector function. The combination therapy of a low dose of TCRtg T cells and mRNA immunotherapy led to robust and durable anti-tumour responses, significantly improving survival compared to monotherapies. Notably, transferred TCRtg T cells expanded only following mRNA immunotherapy, and circulating TCRtg T cells exhibited a memory precursor and effector memory phenotype. These cells infiltrated tumours effectively and displayed more potent cytotoxic activity, resulting in regression of large tumours-even without prior lymphodepletion. Overall, our findings demonstrate that mRNA immunotherapy can substantially enhance the efficacy of TCRtg T cell therapy in a solid tumour model. This combinatorial approach holds promise for overcoming key limitations of ACT by boosting T cell expansion, persistence, infiltration, and functional capacity within the tumour microenvironment.
    Keywords:  Adoptive T cell therapy—ACT; Cancer immunotherapy; Cancer vaccine; Immunotherapy; Transgenic T cell receptor (TCR); mRNA
    DOI:  https://doi.org/10.1038/s41598-026-65120-4
  12. Sci China Life Sci. 2026 Aug 06.
    Menaquinone-4 protects CD8+ T cells from ferroptosis to enhance anti-tumor immunity.
    Jiarong Wang, Wen Wang, Simiao Fan, Liyun Liang, Huaibin Hu, Zenqing Song, Yu Zhang, Jiamei Zhang, Wanying Xiao, Biyu Zhang, Yaxin Li, Liang Luo, Min Wu, Haiqin Tu, Shaoyi Huang, Qiuying Han, Yuqi Wen, Sen Li, Ailing Li, Huiyan Li.
      Tumor-infiltrating CD8+ T cells undergo aberrant lipid accumulation in the tumor microenvironment (TME), which triggers ferroptosis, drives T cell dysfunction, and impairs anti-tumor activity. However, strategies to protect the effector functions of CD8+ T cells by preventing ferroptosis in vivo remain limited. Here, we report that menaquinone-4 (MK-4), a form of vitamin K2, serves as a potent ferroptosis inhibitor that preserves CD8+ T cell function within the TME and enhances anti-tumor activity. Specifically, we demonstrated that MK-4 acts as a potent anti-ferroptotic agent in CD8+ T cells, thereby restoring their effector cytotoxic potential. RNA sequencing (RNA-seq) analysis revealed that MK-4 reprograms the transcriptional landscape of CD8+ T cells by reversing RSL3-induced ferroptosis-related gene expression, restoring effector-associated gene expression, and mitigating dysfunction and exhaustion programs. In adoptive cell transfer models, MK-4 pretreatment effectively suppressed ferroptosis in CD8+ T cells, enhanced their effector functions, and inhibited tumor growth. Similarly, intravenous injection of MK-4 attenuated ferroptosis in endogenous CD8+ T cells and strengthened their anti-tumor capacity. Furthermore, the combination of MK-4 with anti-programmed death-1 (PD-1) antibody therapy elicits a synergistic anti-tumor effect. Collectively, our findings reveal that MK-4 preserves CD8+ T cell function by inhibiting ferroptosis, boosts anti-tumor immunity, thereby highlighting its potential as a therapeutic strategy for cancer treatment.
    Keywords:  CD8+ T cell; anti-tumor immunity; ferroptosis; menaquinone-4
    DOI:  https://doi.org/10.1007/s11427-025-3349-0
  13. Genes Dis. 2026 Nov;13(6): 101737
    DLL3 serves as a pivotal hub bridging malignant progression and immunosuppression in NECC with therapeutic implications validated via the organoid-TIL co-culture system.
    Qinqin Liu, Xinyu Qu, Shuqi Li, Yan Ding, Tingting Ren, Qi'an Jiang, Jingxin Ding, Keqin Hua, Junjun Qiu.
      Neuroendocrine carcinoma of the cervix (NECC) represents a highly aggressive cervical cancer subtype with a poorly characterized tumor immune microenvironment (TIME) and unclear oncogenic mechanisms. Herein, through scRNA-seq analysis, we identified neuronal progenitor cells (NPCs) exhibiting high expression of NECC markers (SYN/INSM1) as putative malignant cells, and delineated three distinct NPC states along their developmental trajectory. Notably, we observed extensive infiltration of both naïve and exhausted T cells, collaboratively shaping an immunosuppressive TIME. Cellular communication analysis discovered DLL3's interaction with NOTCH2 on NPCs and NOTCH1/2 on tumor-infiltrating lymphocytes, with spatial relationships validated by multicolor immunohistochemistry staining. Functional experiments demonstrated that DLL3 promoted tumor cell proliferation and invasion, whereas co-culture assays revealed that DLL3 contributed to T cell exhaustion and impaired T cell activation, collectively proving DLL3 as a central molecular hub coordinating both malignant progression and immunosuppression. Moreover, we verified heightened and specific DLL3 expression in NECC tissues through immunohistochemistry staining, underscoring DLL3 as a promising therapeutic target for NECC. Significantly, we not only innovatively established NECC-derived organoids replicating cellular morphology, neuroendocrine differentiation features, and genetic characteristics of parental tumors, but also co-cultured organoids with tumor-infiltrating lymphocytes to assess the therapeutic efficacy of AMG757 targeting DLL3. Remarkably, the combination of AMG757 targeting DLL3 with chemotherapy (etoposide + cisplatin) induced substantial T cell aggregation and activation and heightened immunogenic cell death, offering novel insights into NECC treatment. Overall, the study provides comprehensive insights into NECC TIME and tailored therapeutic approaches beyond traditional therapy for NECC.
    Keywords:  Neuroendocrine carcinoma of the cervix; Organoid; Precise treatment; TCR-Seq; Tumor microenvironment; scRNA-seq
    DOI:  https://doi.org/10.1016/j.gendis.2025.101737
  14. Cancer Drug Resist. 2026 ;9 26
    Mechanistic roles and clinical applications of tertiary lymphoid structures in colorectal cancer drug resistance.
    Zhiliang Li, Wenqing Jia, Zichao Guo, Fang Zheng, Chenhao Huang, Tao Zhang, Zhuoqing Xu, Haoran Feng, Xi Cheng, Ren Zhao.
      Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate in situ immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically "cold" tumors into "hot" niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.
    Keywords:  Tertiary lymphoid structures; colorectal cancer; drug resistance; immunotherapy; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.20517/cdr.2026.35
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