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

While DNA sensing pathways such as the cGAS-STING axis have been extensively studied, the role of RNA sensors in antitumor immunity remains elusive. Here, we demonstrated that the RNA sensor MDA5 regulates tumor immunity in an adaptive immunity-dependent manner.

MDA5 loss in tumor cells reshapes the tumor microenvironment, resulting in strengthened immune memory responses and enhanced 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.