Targeting MDA5 induces immunogenic cell death and promotes anti-tumor immunity

Identifying targets to enhance tumor immunity is an urgent need. Although nucleic acid sensors play critical roles in promoting tumor immune clearance, their exceptionally low mutation rate in cancers suggests potential unexplored roles in tumor progression. Here, we demonstrate that the RNA sensor melanoma differentiation-associated protein 5 (MDA5) promotes immune evasion, and its high expression is strongly predictive of poor survival and resistance to immune checkpoint blockade (ICB) therapy in patients. Targeting MDA5 reshapes the tumor microenvironment, strengthening immune memory responses and enhancing effector CD8⁺ T cell activity in preclinical models in female mice. Mechanistically, MDA5 deficiency triggers unfolded protein response driven immunogenic cell death through induction of damage-associated molecular patterns, leading to enhanced dendritic cell-mediated antigen engulfment and T cell activation. Additionally, MDA5 loss primes the ASK1-JNK/P38 signaling pathway, sensitizing tumor cells to TNF-α/IFN-γ, further amplifying this process. Consequently, targeting MDA5 enhances the efficacy of ICB therapy across multiple cancer types, positioning it as a promising therapeutic target. RNA sensors have been linked to antitumor immune responses. Here, based on results of in vivo CRISPR screens, the authors propose the RNA sensor MDA5 as a regulator of immune evasion, showing that its targeting induces immunogenic cell death and anti tumor immunity.