Targeting MDA5 enhances tumor immunity through immunogenic cell death and augments the efficacy of immune checkpoint blockade

Abstract

<title>Abstract</title> 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 demonstrated that the RNA sensor MDA5 promotes immune evasion, and its high expression was 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. Mechanistically, MDA5 deficiency triggers UPR-driven immunogenic cell death (ICD) through induction of damage-associated molecular patterns (DAMPs), 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 TNFα/IFNγ, further amplifying this process. Consequently, targeting MDA5 enhances the efficacy of ICB therapy across multiple cancer types, positioning it as a promising therapeutic target.

Affiliated Institutions

• Sun Yat-sen University CN
• Genome Institute of Singapore SG
• Sixth Affiliated Hospital of Sun Yat-sen University CN

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