GDF15-GFRAL axis drives tumor immune evasion by promoting cGAS succinylation
Description
Neutralizing growth differentiation factor 15 (GDF15) with monoclonal antibodies has emerged as a promising immunotherapeutic strategy for solid tumors; but the underlying mechanisms remain unclear. Here, we discover that glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL)—conventionally considered a brainstem‑restricted receptor—is ectopically expressed on tumor cells, where it drives immune evasion. Mechanistically, GDF15 binding to tumor GFRAL induces site‑specific succinylation of cyclic GMP‑AMP synthase (cGAS) at lysine 164 (K164), which impairs cGAS dimerization and enzymatic activity, thereby suppressing cGAS‑mediated innate immunity and subsequent CD8⁺ T cell activation. Genetic ablation of GFRAL or GDF15 enhances antitumor immunity and sensitizes tumors to programmed cell death protein 1 (PD-1) blockade. Importantly, therapeutic targeting of GFRAL with the monoclonal antibody JMT203 effectively inhibits cGAS K164 succinylation and synergizes with anti-PD-1 therapy to suppress tumor growth in preclinical models. Clinically, cGAS K164 succinylation levels correlate with reduced CD8⁺ T cell infiltration and poor patient survival, highlighting its potential as a prognostic biomarker. Thus, our study identifies GDF15-GFRAL signaling as a critical regulator of cGAS signalling and establishes GFRAL as a promising target for overcoming immunotherapy resistance.