The TNFR2M196R germline variant confers dual impact on CAR-T cell immunotherapy by enhancing T-cell survival and tumor proliferation.

Despite its remarkable efficacy in hematologic malignancies, chimeric antigen receptor T-cell (CAR-T) therapy is often limited by atypical clinical outcomes, necessitating predictive biomarkers. Here, prompted by a patient with low-tumor-burden non-Hodgkin lymphoma who develops severe and persistent cytokine release syndrome (CRS), we identify the germline TNFR2M196R single-nucleotide polymorphism, rs1061622, as a candidate genetic determinant of atypical responses. The TNFR2M196R variant is found to enhance the antitumor efficacy of CAR-T cells by reducing their apoptosis. Paradoxically, however, patients carrying the TNFR2M196R variant exhibit higher rates of early tumor progression. Further investigation reveals that while the TNFR2M196R mutation increases tumor susceptibility to CAR-T-mediated killing, it also accelerates tumor proliferation kinetics. Together, these results establish the TNFR2M196R SNP as a dual-function genetic determinant that modulates both CAR-T cell efficacy and intrinsic tumor behavior, highlighting the critical impact of germline genetics on cancer immunotherapy.