Inducing tumor-intrinsic innate immune response to break cancer immunotherapy resistance

Immune checkpoint blockade (ICB) therapy targeting the PD-1/PD-L1 axis has dramatically transformed cancer treatment. However, durable responses are limited to a subset of patients, particularly for those with solid tumors. Therefore, understanding the resistance mechanisms and developing a novel therapeutic strategy are urgent priorities. The tumor microenvironment (TME) is a key determinant of ICB therapy responsiveness, and resistance mechanisms are heterogeneous. Recent studies have shown that a major contributor to resistance is an immunologically "cold" TME that contains very few infiltrating immune cells. Inducing tumor-intrinsic innate immune responses through the viral mimicry response, in which cytoplasmic nucleic acid sensors are activated by aberrantly accumulated nucleic acids, represents a promising strategy to convert "cold" tumors to "hot" (immune-inflamed) and enhance ICB efficacy. In this review, we summarize the current understanding of TME-mediated resistance to ICB and introduce therapeutic approaches that trigger viral mimicry responses in cancer cells, including epigenetic therapies, agents that perturb nucleic acid metabolism, and DNA damage inducers, and discuss opportunities for combining viral mimicry-based strategies with ICB therapy to overcome resistance.