ROCK1 inhibition primes anti-tumor immunity in EGFR-mutant NSCLC by triggering PD-L1 degradation mediated by SMURF2.

Abstract

Epidermal growth factor receptor (EGFR) mutations are common in non-small-cell lung cancer (NSCLC) but typically confer poor responses to immunotherapy, likely owing to an inhibitory tumor immune microenvironment. Here, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) was identified as having significantly elevated kinase activity in EGFR-mutant NSCLC through phosphoproteomic analyses. Inhibition of ROCK1, while only mildly suppressing tumor cell proliferation, markedly enhances CD8 + T cell-mediated antitumor immune responses in vitro and in vivo. Mechanistically, ROCK1 inhibition suppresses PD-L1 expression via GSK3α-mediated phosphorylation of PD-L1 at serine 283, promoting its ubiquitination and degradation by the E3 ubiquitin ligase SMURF2. This process enhances the cytotoxic activity of CD8 + T cells. Furthermore, combining ROCK1 inhibitors with PD-L1 blockade produces substantial anti-tumor efficacy in EGFR-mutant NSCLC mouse models. Collectively, our findings reveal a critical role for ROCK1 in regulating the tumor immune microenvironment and highlight that targeting ROCK1 could improve immunotherapy outcomes in patients with EGFR-mutant NSCLC.