GSDMB synergizes anti-PD-1 efficacy via Sema7a-mediated CD8+ T Cell infiltration in bladder cancer

Abstract

Gasdermin B (GSDMB) is highly expressed in bladder cancer (BLCA) and has been implicated in anti-tumor immunity, yet its functional role and underlying mechanisms in enhancing the efficacy of immune checkpoint inhibitors (ICIs) remain unclear. Herein, we demonstrate that GSDMB synergizes the efficacy of ICI therapy in BLCA through promoting the infiltrating of CD8⁺ T cells in the tumor microenvironment (TME) and enhancing expression of interferon-γ (γ-IFN), tumor necrosis factor-α (TNF-α), and granzyme B (GZMB) in tumor-infiltrating CD8 + T cells. Mechanistically overexpression of GSDMB leads to its translocation to the nucleus, where it interacts with DEAD-box helicase 5 (DDX5) to upregulate the expression of Semaphorin 7A (Sema7a). Secreted Sema7a subsequently facilitates the recruitment of CD8⁺ T cells into the TME and augments anti-tumor immunity against BLCA. Our findings thus reveal a novel mechanism by which GSDMB functions as a transcriptional regulator via GSDMB-DDX5 interaction to promote Sema7a transcription and identify the GSDMB–DDX5–Sema7a-CD8 + T axis as a mechanism linking tumor-intrinsic signaling to enhance anti-tumor immunity and improve anti-PD-1 response. These findings suggest that GSDMB may serve as a potential prognostic biomarker for outcomes in patients with BLCA treated with anti-PD-1.