The TNFR2<sup>M196R</sup> germline variant confers dual impact on CAR-T cell immunotherapy by enhancing T-cell survival and tumor proliferation

Nan Liu; Lu Han; Yuting Lu; Yelei Guo; Jiajia Li; Qi Zhu; Yao Wang; Zhiqiang Wu; Xin Lin; Jianshu Wei; Weidong Han

doi:10.1016/j.jgg.2026.05.014

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The TNFR2^M196R germline variant confers dual impact on CAR-T cell immunotherapy by enhancing T-cell survival and tumor proliferation

doi: 10.1016/j.jgg.2026.05.014

a. Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China;
b. Changping Laboratory, Beijing 102206, China;
c. School of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing 100084, China;
d. Tsinghua-Peking Center for Life Sciences, Beijing 100871, China

Funds:

This work was supported by the National Natural Science Foundation of China (82341208 and 82430012 to W.H.) and the Changping Laboratory annual fund to X.L.

Received Date: 2025-12-26
Accepted Date: 2026-05-30
Rev Recd Date: 2026-05-23

Available Online: 2026-06-06

Abstract

Abstract

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 TNFR2^M196R single-nucleotide polymorphism, rs1061622, as a candidate genetic determinant of atypical responses. The TNFR2^M196R variant is found to enhance the antitumor efficacy of CAR-T cells by reducing their apoptosis. Paradoxically, however, patients carrying the TNFR2^M196R variant exhibit higher rates of early tumor progression. Further investigation reveals that while the TNFR2^M196R mutation increases tumor susceptibility to CAR-T-mediated killing, it also accelerates tumor proliferation kinetics. Together, these results establish the TNFR2^M196R 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.
- CAR-T cells,
- TNFR2^M196R,
- Germline variant,
- Apoptosis,
- Proliferation,
- Biomarker

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