Targeting BATF2-RGS2 axis reduces T-cell exhaustion and restores anti-tumor immunity.

OBJECTIVE: This study aims to investigate the role of RGS2 in immune regulation in lung cancer (LC) and explore the regulatory relationship between RGS2 and BATF2 in modulating T cell exhaustion and tumor immune evasion. METHODS: Single-cell transcriptome-based analysis was performed to identify CD8(+) T-cell profiles and regulatory factors in six LC patients receiving neoadjuvant PD-1 blockade therapy. Mouse 3LL cells or murine tumor organoid models were transplanted into wild-type, RGS2 knock-out (RGS2(-/-)), or BATF2 knock-out (BATF2(-/-)) mice to analyze the effects of RGS2 and BATF2 on tumor growth, metastasis, and immune cell infiltration. CD8(+) from these mice were isolated and co-cultured with cancer cells to analyze T cell cytotoxicity in vitro. The transcriptional regulation of RGS2 by BATF2 was analyzed using luciferase reporter assays. RESULTS: RGS2 was highly expressed in CD8(+) T-exhausted (Tex) cells and was associated with pro-inflammatory pathways. High RGS2 expression predicted poor clinical outcomes and limited response to PD-1/PD-L1 blockade therapy. In RGS2(-/-) mice, tumor metastasis and angiogenesis were suppressed, CD8(+) effector T cells were enhanced, and T cell exhaustion markers were reduced. BATF2 was identified as a key transcriptional regulator of RGS2, promoting T cell exhaustion through inhibition of CXCL13 secretion. Knockdown of BATF2 or RGS2 impaired lung cancer cell proliferation and enhanced sensitivity to NK cell-mediated cytotoxicity in vitro. In BATF2(-/-) mice, the populations of immune active CD8(+) T cells were increased, while exhausted T cells were reduced, leading to improved anti-tumor immune responses. CONCLUSIONS: RGS2, regulated by BATF2, plays a critical role in driving T cell exhaustion and tumor immune evasion in LC. Targeting the BATF2-RGS2 axis may enhance the effectiveness of immunotherapy by reversing T cell exhaustion and improving anti-tumor immunity.