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RNA-seq, RT-qPCR, and an immunological memory mouse model further support impaired tumor rejection after prior anti–PD-L1 cure, suggesting reduced effector memory T cell 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75:33 [https://doi.org/10.1007/s00262-025-04279-7](https://doi.org/10.1007/s00262-025-04279-7)  \nAfatinib exerts an inhibitory effect onT cell‑mediated cytotoxicity  \nMasaru Yokomura1,2 · Seiji Nagano3 · Hiroshi Kawamoto3 · Yoshihiko Hirohashi4 · Toshihiko Torigoe4 · Takahiro Asakage2 · Ryohei Katayama1,5  \nReceived: 14 August 2025 / Accepted: 17 December 2025 / Published online: 3 January 2026 © The Author(s) 2025  \nAbstract  \nAdoptive T cell therapy has shown significant efficacy in cancer treatment, especially in hematologic malignancies, and is increasingly being explored for solid cancers. Combining T cell therapy with conventional treatments holds promise for enhancing therapeutic effects. In this study, we conducted an in vitro inhibitor screening to evaluate the effects of various inhibitors on T cell-mediated cytotoxic activity against cancer cells. Among the candidates, we identified afatinib as an immunosuppressive agent that attenuates T cell cytotoxic activity by reducing interferon-γ (IFN-γ) secretion and suppressing T cell activation. Notably, this IFN-γ reduction was independent of T cell proliferation. RNA-seq analysis revealed that afatinib downregulated the T cell receptor (TCR) pathway signature. RT-qPCR demonstrated a dose-dependent suppression of IFNG mRNA expression in afatinib-treated T cells. Furthermore, afatinib impaired tumor rejection in an immunological memory mouse model that had been previously cured by anti–PD-L1 therapy, suggesting that afatinib may inhibit the function of effector memory T cells. Collectively, our findings highlight afatinib’s potential to impair T cell effector functions, indicating that strategic consideration is essential when combining epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), including afatinib, with adoptive T cell therapies.  \nKeywords Afatinib · Inhibitory effect · T cell therapy · IFN-γ secretion  \nIntroduction  \nAdoptive T cell therapy, a form of immunotherapy, has shown promise in cancer treatment, particularly with the clinical success of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies such as B-cell lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma  \n* Ryohei Katayama [ryohei.katayama@jfcr.or.jp](ryohei.katayama@jfcr.or.jp)  \n1 Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-Ku, Tokyo 135-8550, Japan  \n2 Department of Head and Neck Surgery, Institute of Science Tokyo, Tokyo, Japan  \n3 Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan  \n4 Department of Pathology, School of Medicine, Sapporo Medical University, Sapporo, Japan  \n5 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan  \n(DLBCL) [1, 2] . Recent studies have expanded its application beyond hematologic cancers. TCR-engineered T cells and tumor-infiltrating lymphocyte (TIL) therapies have demonstrated potential in solid tumors, including melanoma, sarcoma, and non-small cell lung cancer (NSCLC)[3–7] . Although challenges remain—such as tumor antigen heterogeneity, poor T cell infiltration, and an immunosuppressive tumor microenvironment—novel strategies like targeting shared neoantigens, enhancing T cell trafficking, and modulating the tumor microenvironment are being explored to overcome these barriers [3] . Furthermore, several studies have shown that adoptive T cell therapy is more effective in treatment-naive patients, as prior therapies can impair T cell function and reduce efficacy [8, 9] . Thus, combining T cell therapy with conventional treatments as an initial strategy may offer therapeutic benefits [10, 11] .  \nCurrently, adoptive T cell therapies are primarily performed in an autologous setting, where peripheral T cells are collected from each patient, expanded, and genetically modified. This process in","cbCaioUQcTCzlUu3","https://ap.wps.com/l/cbCaioUQcTCzlUu3","pdf",3935029,13,"English","# Abstract\n# Introduction","[{\"question\":\"What was the goal of the in vitro inhibitor screening in this study?\",\"answer\":\"To evaluate how various inhibitors affect T cell-mediated cytotoxic activity against cancer cells and assess their compatibility with adoptive T cell therapy when combined with conventional treatments.\"},{\"question\":\"How does afatinib impair T cell-mediated cytotoxicity?\",\"answer\":\"Afatinib attenuates T cell cytotoxic activity by reducing interferon-γ (IFN-γ) secretion and suppressing T cell activation.\"},{\"question\":\"Is afatinib’s effect dependent on T cell proliferation?\",\"answer\":\"No. The IFN-γ reduction reported for afatinib is independent of T cell proliferation, and it includes dose-dependent suppression of IFNG mRNA expression.\"}]","Afatinib exerts an inhibitory effect on T cell-mediated cytotoxicity | PDF",1790653377,33]