bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–05–04
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. IL2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL15.
  2. Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.
  3. Advances and challenges in cancer immunotherapy: Strategies for personalized treatment.
  4. Prognostic and recurrence risk predictive values of tumor infiltrating lymphocytes in HER2-low breast cancer.
  5. Immune microenvironment of tumor-draining lymph nodes: insights for immunotherapy.
  6. Prognostic Value of CD8+ T Cells at the Invasive Margin Is Comparable to the Immune Score in Nonmetastatic Colorectal Cancer: A Prospective Multicentric Cohort Study.
  7. A Pan-Cancer Comparative Analysis of The Cancer Genome Atlas Transcriptomic TIL-Immune Signatures.
  8. Multifaceted functions of tissue-resident memory T cells in tumorigenesis and cancer immunotherapy.
  9. Optimizing Immunotherapy: The Synergy of Immune Checkpoint Inhibitors with Artificial Intelligence in Melanoma Treatment.
  10. Unlocking tumor-infiltrating lymphocyte potential with CRISPR-Cas9.
  11. Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy.
  12. Neoantigen-based immunotherapy: advancing precision medicine in cancer and glioblastoma treatment through discovery and innovation.
  13. Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.
  14. Dual cytokine-engineered macrophages rejuvenate the tumor microenvironment and enhance anti-PD-1 therapy in renal cell carcinoma.
  1. Mol Ther. 2025 Apr 24. pii: S1525-0016(25)00310-7. [Epub ahead of print]
    IL2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL15.
    Rachel A Burga, Bulent Arman Aksoy, Zheng Ao, Jeremy H Tchaicha, Dhruv K Sethi, Alonso Villasmil Ocando, Gauri S Kulkarni, Scott Lajoie, Kyle D Pedro, Jack Ryan Tremblay, Meghan Langley, Benjamin Primack, Violet A Young, Theresa Ross, Mithun Khattar, Dexue Sun, Dan Jun Li, Shyam Subramanian, Michelle Ols, Jan Ter Meulen.
      Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated great potential for patients with treatment-refractory metastatic melanoma. However, the need for interleukin 2 (IL2) co-administration during TIL cell therapy limits patient eligibility and restricts treatment to intensive care units due to the risk of severe side effects. Instead, engineering TIL with membrane-bound interleukin 15 (mbIL15) has the potential to promote TIL expansion, antitumor activity, and persistence of CD8+ T cells, without the use of IL2. cytoTIL15™ cells express mbIL15 fused to a drug-responsive domain (DRD) that is regulated by the FDA-approved small-molecule drug acetazolamide (ACZ). As such, cytoTIL15 cells are manufactured with ACZ instead of IL2, in the presence of engineered feeder cells. The cytoTIL15 cell product exhibits ACZ dose-dependent expansion and persistence in vitro and in vivo and potent tumor-killing activity in human melanoma models in the absence of IL2. In patient-derived xenograft (PDX) tumors, spatial profiling revealed infiltrating cytoTIL15 cells to be highly cytotoxic and less exhausted than non-engineered TIL. This novel platform creates a powerful, IL2-free TIL cell therapy with a potentially improved tolerability and safety profile, while allowing individualized pharmacologic regulation of the TIL product.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.04.031
  2. Cell Rep Med. 2025 Apr 25. pii: S2666-3791(25)00169-7. [Epub ahead of print] 102096
    Tumor-infiltrated double-negative regulatory T cells predict outcome of T cell-based immunotherapy in nasopharyngeal carcinoma.
    Xiu-Feng Liu, Bin Song, Chang-Bin Sun, Qian Zhu, Jian-Hui Yue, Yu-Jing Liang, Jia He, Xi-Liang Zeng, Ye-Chi Qin, Qiu-Yan Chen, Hai-Qiang Mai, Xi Zhang, Jiang Li.
      Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated clinical success in solid tumors. We analyze 47 TIL infusion products and 62 pretreatment tumor microenvironments (TMEs) from a randomized phase 2 clinical study of concurrent chemoradiotherapy plus TIL-ACT (NCT02421640). Using single-cell and bulk RNA sequencing along with flow cytometry, we identify 14 CD3+ T cell clusters within 26 TIL infusion products: 11 CD3+CD8+ TILs, 2 CD3+CD4+ TILs, and 1 CD3+CD8-CD4- double-negative (DN) TIL. (DN) TILs, significantly associated with poor TIL-ACT outcomes, exhibit an activated regulatory T cell-like phenotype and include two CD56+ and four CD56- subsets. Among them, CD56-KZF2+ (DN) TILs are predominantly suppressive. (DN) TILs inhibit CD8+ TIL expansion via Fas-FasL, transforming growth factor β (TGF-β), and interleukin (IL)-10 signaling. Distinct CD8+ T subsets differentially impact on TIL-ACT outcomes, while 9 baseline TME gene signatures and 14 intracellular T cell genes hold prognostic value. Our findings identify predictive TIL subsets and biomarkers for TIL-ACT outcomes.
    Keywords:  TIL infusion products; adoptive cell therapy; double-negative T cells; nasopharyngeal carcinoma; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102096
  3. Semin Oncol. 2025 Apr 29. pii: S0093-7754(25)00037-5. [Epub ahead of print]52(3): 152345
    Advances and challenges in cancer immunotherapy: Strategies for personalized treatment.
    Mahir Azmal, Md Munna Miah, Fatema Sultana Prima, Jibon Kumar Paul, Anm Shah Newaz Been Haque, Ajit Ghosh.
      Cancer immunotherapy has transformed oncology by harnessing the immune system to specifically target cancer cells, offering reduced systemic toxicity compared to traditional therapies. This review highlights key strategies, including adoptive cell transfer (ACT), immune checkpoint inhibitors, oncolytic viral (OV) therapy, monoclonal antibodies (mAbs), and mRNA-based vaccines. ACT reinfuses enhanced immune cells like tumor-infiltrating lymphocytes (TILs) to combat refractory cancers, while checkpoint inhibitors (eg, PD-1 and CTLA-4 blockers) restore T-cell activity. OV therapy uses engineered viruses (eg, T-VEC) to selectively lyse cancer cells, and advanced mAbs improve targeting precision. mRNA vaccines introduce tumor-specific antigens to trigger robust immune responses. Despite significant progress, challenges like immune-related side effects, high costs, and immunosuppressive tumor microenvironments persist. This review underscores the need for combination strategies and precision medicine to overcome these barriers and maximize the potential of immunotherapy in personalized cancer treatment.
    Keywords:  Adaptive immunity; Adoptive cell transfer; Cancer immunotherapy; Immunosuppressive microenvironments; Innate immunity; Vaccine
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152345
  4. Clin Transl Oncol. 2025 Apr 27.
    Prognostic and recurrence risk predictive values of tumor infiltrating lymphocytes in HER2-low breast cancer.
    Lijun Song, Xiangjun Li, Lulu Wang, Jian Cui, Teng Ma.
       BACKGROUND: With the emergence of novel anti-HER2 antibody drug conjugates, patients with HER2-low breast cancer have received increased attention. Tumor-infiltrating lymphocytes (TILs) are significantly associated with survival benefits in cancers. However, their prognostic value in patients with low her2 breast cancer is unknown. Therefore, we aimed to determine the relationship between TILs and recurrence in patients with HER2-low breast cancer.
    METHODS: Clinicopathological data were retrospectively collected from patients with human epidermal growth factor receptor 2 (HER2) low-expression breast cancer who underwent consultations at Qingdao University Affiliated Hospital. We determined the correlation between TILs and disease-free survival (DFS) followed by the threshold value of TILs using X-tile software. Survival was assessed using Kaplan-Meier analysis, and cox regression analysis was performed for recurrence risk modeling.
    RESULTS: Our study showed a 15% TIL level was the optimal cutoff for DFS. The low and high TILs survival curves showed significant differences in the log-rank test (p = 0.009). Cox regression analyses found that lymph node stage, histologic grading, TILs, and Ki-67 were independent variables influencing the prognosis (p < 0.05). On this basis, we developed a risk prediction model to accurately predict the 3- and 5-year disease-free survival rates of patients with HER2-low breast cancer, the model demonstrated good overall performance.
    CONCLUSION: TILs are associated with recurrence in patients with breast cancer and low HER2 levels. TILs > 0.15 is a reliable indicator of DFS. For patients with low TILs (≤ 0.15), extensive follow-up is required. These findings provide a basis for targeted, individualized treatment.
    Keywords:  Breast cancer; Disease-free survival; Human epidermal growth factor receptor 2; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s12094-025-03921-1
  5. Front Immunol. 2025 ;16 1562797
    Immune microenvironment of tumor-draining lymph nodes: insights for immunotherapy.
    Jiahuan Wei, Daozhang Li, Haixia Long, Mei Han.
      Tumor-draining lymph nodes (TDLNs) play a crucial role in modulating tumor immune responses and influencing the efficacy of immunotherapy. However, our current understanding of the microenvironment within these lymph nodes remains limited. Tumors not only impair the anti-tumor activity of CD8+ T cells by creating an immunosuppressive microenvironment, but they also facilitate immune evasion and promote metastasis by altering the structure and function of TDLNs. Research has shown that tumor-specific memory CD8+ T cells (TTSM) within TDLNs are essential for the efficacy of immune checkpoint inhibitors, such as PD-1/PD-L1 blockers. Moreover, the abnormal structure of TDLNs, along with the presence of immunosuppressive cells-such as regulatory T cells (Tregs), regulatory B cells (Bregs), and immunosuppressive dendritic cells (DCs)-contributes to tumor-mediated immune evasion. Therefore, gaining a deeper understanding of the immune microenvironment within TDLNs is essential for improving the effectiveness of immunotherapies and developing novel therapeutic strategies. This review explores various TDLN-based therapeutic strategies, addressing the controversies surrounding lymph node dissection, the use of TDLNs as a source of tumor-infiltrating lymphocytes (TILs) for therapy, targeting immunosuppressive cells within TDLNs, and methods to reverse the structural abnormalities of TDLNs. These strategies offer valuable insights and potential directions for advancing tumor immunotherapy.
    Keywords:  CD8+ T cells; PD-L1/PD-1; immune microenvironment; immunosuppressive cells; immunotherapy; tumor-draining lymph nodes
    DOI:  https://doi.org/10.3389/fimmu.2025.1562797
  6. Clin Cancer Res. 2025 May 01. 31(9): 1711-1718
    Prognostic Value of CD8+ T Cells at the Invasive Margin Is Comparable to the Immune Score in Nonmetastatic Colorectal Cancer: A Prospective Multicentric Cohort Study.
    Durgesh Wankhede, Niels Halama, Matthias Kloor, Dominic Edelmann, Hermann Brenner, Michael Hoffmeister.
       PURPOSE: The Immunoscore predicts colorectal cancer prognosis but faces adoption barriers because of complex software and reimbursement issues. This study used open-source methods to explore a simplified prognostic model in nonmetastatic colorectal cancer by focusing on single T-cell markers.
    EXPERIMENTAL DESIGN: A multicentric prospective cohort study in patients with nonmetastatic colorectal cancer assessed CD3+ and CD8+ tumor-infiltrating lymphocytes (TIL) in the invasive margin (IM) and tumor core (TC) using QuPath. An immune cell score (ICS), based on TIL densities (CD3-IM, CD8-IM, CD3-TC, and CD8-TC), was calculated similarly to the Immunoscore. A split sample approach (70:30) estimated adjusted HRs for cancer-specific survival in training and validation sets. Classification and regression tree analysis identified the most prognostic TIL, and its model was compared with an ICS model for performance (Brier score) and discrimination (concordance probability estimate).
    RESULTS: Over a median follow-up of 9.0 years, 203 colorectal cancer-specific deaths occurred among 1,260 patients. Classification and regression tree-selected CD8-IM was the most prognostic TIL at a cutoff of 231 cells/mm2. Patients with high CD8-IM had better cancer-specific survival than low CD8-IM in both training (HR 0.58, 95% confidence interval, 0.40-0.84) and validation sets (HR 0.35, 95% confidence interval, 0.21-0.60). Brier scores of CD8-IM and ICS survival models were comparable in both training and validation cohorts, whereas the survival discrimination of CD8-IM slightly outperformed the ICS in the validation set (concordance probability estimate: CD8-IM: 0.748; ICS: 0.730).
    CONCLUSIONS: CD8-IM alone provided prognostic information comparable with the ICS. Simplified, cost-effective TIL assessments could improve clinical translation and guide adjuvant therapy in early-stage colorectal cancer.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3275
  7. Res Sq. 2025 Apr 25. pii: rs.3.rs-6441170. [Epub ahead of print]
    A Pan-Cancer Comparative Analysis of The Cancer Genome Atlas Transcriptomic TIL-Immune Signatures.
    Kyle Hitscherich, Darryl Noussome, Aaron Dinerman, Victoria Dulemba, Frank Lowery, Naris Nilubol.
      Efforts to understand the tumor microenvironment (TME) through basic science research and The Cancer Genome Atlas (TCGA) data analysis have led to the creation of unique immune transcriptomic signatures from tumor-infiltrating lymphocytes (TIL). However, no pan-cancer analysis has been conducted to compare the prognostic performance of these signatures using overall survival (OS) or progression-free interval (PFI) as endpoints. We compiled a library of 146 TIL-immune signatures and evaluated gene signature score correlation with OS and PFI for 9,961 available TCGA samples across 33 cancer types. Zhang CD8 TCS demonstrated higher accuracy in prognosticating both OS and PFI across the pan-cancer landscape, however, variability was seen across cancer types and germ cell origin. Cluster analysis compiled a group of six signatures (Oh.Cd8.MAIT, Grog.8KLRB1, Oh.TIL_CD4.GZMK, Grog.CD4.TCF7, Oh.CD8.RPL, Grog.CD4.RPL32) whose association with OS and PFI could potentially be conserved across multiple cancer types.
    DOI:  https://doi.org/10.21203/rs.3.rs-6441170/v1
  8. Cancer Immunol Immunother. 2025 Apr 26. 74(6): 184
    Multifaceted functions of tissue-resident memory T cells in tumorigenesis and cancer immunotherapy.
    Eun Sang Seo, Sung-Kyu Lee, Young Min Son.
      Tissue-resident memory T (TRM) cells are well reported as a strong protective first line of defense against foreign antigens in non-lymphoid tissues. Moreover, TRM cells have demonstrated critical protective roles in antitumor immunity, contributing to enhanced survival and tumor growth inhibition across various cancer types. However, surprisingly, recent studies suggest that TRM cells can exhibit paradoxical effects, potentially promoting tumor progression under certain conditions and leading to adverse outcomes during antitumor immune responses. Understanding the complexities of TRM cell functions will enable us to harness their potential in advancing cancer immunotherapy more effectively. Therefore, this review comprehensively investigates the dual roles of TRM cells in different tumor contexts, highlighting their protective functions in combating cancers and their unfavorable potential to exacerbate tumor development. Additionally, we explore the implications of TRM cell behaviors for future cancer treatment strategies, emphasizing the need for further research to optimize the therapeutic exploitation of TRM cells while mitigating their deleterious effects.
    Keywords:  CD103+ lymphocytes; Cancer immunotherapy; Tissue-resident memory T (TRM) cells; Tumor-infiltrating lymphocytes (TILs); Tumorigenesis
    DOI:  https://doi.org/10.1007/s00262-025-04035-x
  9. Biomolecules. 2025 Apr 16. pii: 589. [Epub ahead of print]15(4):
    Optimizing Immunotherapy: The Synergy of Immune Checkpoint Inhibitors with Artificial Intelligence in Melanoma Treatment.
    Mohammad Saleem, Abigail E Watson, Aisha Anwaar, Ahmad Omar Jasser, Nabiha Yusuf.
      Immune checkpoint inhibitors (ICIs) have transformed melanoma treatment; however, predicting patient responses remains a significant challenge. This study reviews the potential of artificial intelligence (AI) to optimize ICI therapy in melanoma by integrating various diagnostic tools. Through a comprehensive literature review, we analyzed studies on AI applications in melanoma immunotherapy, focusing on predictive modeling, biomarker identification, and treatment response prediction. Key findings highlight the efficacy of AI in improving ICI outcomes. Machine learning models successfully identified prognostic cytokine signatures linked to nivolumab clearance. The combination of AI with RNAseq analysis had the potential for the development of personalized treatment with ICIs. A machine learning-based approach was able to assess the risk-benefit ratio for the prediction of immune-related adverse events (irAEs) using the electronic health record (EHR) data. Deep learning algorithms demonstrated high accuracy in tumor microenvironment analysis, including tumor region identification and lymphocyte detection. AI-assisted quantification of tumor-infiltrating lymphocytes (TILs) proved prognostically valuable in primary melanoma and predictive of anti-PD-1 therapy response in metastatic cases. Integrating multiple diagnostic modalities, such as CT imaging and laboratory data, modestly enhanced predictive performance for 1-year survival in advanced cancers treated with immunotherapy. These findings underscore the potential of AI-driven approaches to refine biomarker identification, treatment prediction, and patient stratification in melanoma immunotherapy. While promising, clinical validation and implementation challenges remain.
    Keywords:  PD-1; PD-L1; artificial intelligence; immune checkpoint inhibitors; immunotherapy; melanoma
    DOI:  https://doi.org/10.3390/biom15040589
  10. Lancet Oncol. 2025 Apr 15. pii: S1470-2045(25)00145-7. [Epub ahead of print]
    Unlocking tumor-infiltrating lymphocyte potential with CRISPR-Cas9.
    Özcan Met, Inge Marie Svane.
      
    DOI:  https://doi.org/10.1016/S1470-2045(25)00145-7
  11. Res Sq. 2025 Apr 10. pii: rs.3.rs-6215345. [Epub ahead of print]
    Engineering an in vivo charging station for CAR-redirected invariant natural killer T cells to enhance cancer therapy.
    Song Li, Yan-Ruide Li, Haochen Nan, Zeyang Liu, Ying Fang, Yichen Zhu, Zibai Lyu, Zhengyao Shao, Enbo Zhu, Bo Zhang, Youcheng Yang, Xinyuan Shen, Yuning Chen, Tzung Hsiai, Lili Yang.
      Invariant natural killer T (iNKT) cells are a distinct subset of T lymphocytes that possess unique properties making them highly suitable for addressing the challenges of solid tumor immunotherapy. Unlike conventional T cells, which are restricted by polymorphic major histocompatibility complex (MHC) molecules and recognize peptide antigens, iNKT cells are restricted by the non-polymorphic CD1d molecule and respond to lipid antigens. Chimeric antigen receptor (CAR)-redirected iNKT (CAR-iNKT) cells represent a significant advancement in cancer immunotherapy. However, optimizing sustained activation and long-term persistence of CAR-iNKT cells remains a critical need for effective solid tumor treatment. To address these limitations, we develop the iNKT cell-targeted microparticle recruitment and activation system (iMRAS), a biomimetic platform designed to enhance iNKT cell functionality through localized immunostimulation in vivo. This biomimetic platform is designed to function as an in vivo "charging station" containing chemotactic and activation signals for the recruitment, activation, and expansion of CAR-iNKT cells, leading to more effective tumor killing and longer persistence of CAR-iNKT cells, as demonstrated in the therapy of lymphoma and melanoma. Through its biomimetic design and localized immunostimulatory effects, iMRAS helps overcome the limitations of current therapies for solid tumors, establishing a robust platform for enhancing systemic CAR-iNKT cell-mediated immunotherapy.
    DOI:  https://doi.org/10.21203/rs.3.rs-6215345/v1
  12. Explor Target Antitumor Ther. 2025 ;6 1002313
    Neoantigen-based immunotherapy: advancing precision medicine in cancer and glioblastoma treatment through discovery and innovation.
    Moawiah M Naffaa, Ola A Al-Ewaidat, Sopiko Gogia, Valiko Begiashvili.
      Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.
    Keywords:  AI-driven tools; CAR-T; Neoantigen-based immunotherapy; cancer; glioblastoma; precision medicine; tumor microenvironment; tumor-infiltrating lymphocyte therapy
    DOI:  https://doi.org/10.37349/etat.2025.1002313
  13. Front Cell Dev Biol. 2025 ;13 1577081
    Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia.
    Wael Gamal, Melanie Mediavilla-Varela, Vishaal Kunta, Eva Sahakian, Javier Pinilla-Ibarz.
      T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.
    Keywords:  CAR T cell; CLL (chronic lymphocytic leukemia); T-cell exhaustion; adoptive cell immunotherapy; cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2025.1577081
  14. Int Immunopharmacol. 2025 Apr 27. pii: S1567-5769(25)00715-5. [Epub ahead of print]156 114725
    Dual cytokine-engineered macrophages rejuvenate the tumor microenvironment and enhance anti-PD-1 therapy in renal cell carcinoma.
    Xin Liu, Ranran Jiang, Yujun Xu, Xiaodi Xu, Lin Fang, Ge Gao, Lulu Han, Yuxin Chen, Hongwei Du, Ying Cai, Fei Zhu, Mingjing Chen, Kaidi Wang, Hailong Li, Gang Wang, Changyi Quan.
      Despite advances in PD-1 blockade therapy, the immunosuppressive tumor microenvironment (TME) limits its efficacy in renal cell carcinoma (RCC). Here, we developed dual-cytokine-engineered macrophages co-delivering IL-12 and CXCL-9 to reprogram TME and enhance anti-PD-1 responsiveness. Single-cell RNA sequencing revealed that RCC harbor abundant M2-like tumor-associated macrophages (TAMs), which correlate with T-cell exhaustion. In vitro, engineered macrophages polarized M2-like TAMs to antitumor M1 phenotypes, secreted CXCL-9 to recruit cytotoxic T cells, and released IL-12 to amplify T/NK cell activation. In vivo, intravenously administered engineered macrophages homed to tumors, reshaped the TME by increasing CD8+ T cells, dendritic cells, and NK cells while reducing immunosuppressive Tregs and MDSCs. This approach synergized with PD-1 blockade, resulting in a 2.5-fold greater tumor growth inhibition compared to anti-PD-1 monotherapy. This dual-cytokine macrophage platform offers a novel strategy to overcome resistance to checkpoint inhibitors in RCC by delivering cytokine and remodeling TME, with implications for clinical translation.
    Keywords:  Macrophage; PD-1 inhibitor; Renal cell carcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2025.114725
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