Targeting innate immunity in cancer: mechanistic foundations, therapeutic vaccination, and clinical translation

Abstract

Cancer evolves within tissue ecosystems in which innate immune surveillance and tumor-promoting inflammation jointly shape disease progression and therapeutic response. Innate receptors detect cellular stress, altered-self ligands, damaged-cell products and tumor-derived nucleic acids, thereby initiating cytotoxicity, phagocytosis, antigen presentation and adaptive immune priming. However, tumors can redirect these mechanisms through suppressive cytokines, metabolic competition, hypoxia and dysregulated chemokine networks, promoting immune exclusion, metastasis and treatment resistance. This Review examines innate recognition, immunoediting and innate–adaptive crosstalk. We discuss the heterogeneity, dysfunction and therapeutic targeting of dendritic cells, macrophages, natural killer cells, neutrophils, myeloid-derived suppressor cells, innate lymphoid cells and other tissue-resident populations. We also evaluate Toll-like receptor, cGAS–STING, RIG-I–MAVS, inflammasome and complement pathways as therapeutically actionable but potentially tumor-promoting signaling systems. Finally, we consider how innate adjuvants, antigen selection, delivery technologies and rational combinations can improve therapeutic cancer vaccines. Emerging clinical studies demonstrate feasibility, but inconsistent efficacy and treatment-associated toxicity emphasize the need for biomarker-guided patient selection, spatially restricted delivery and mechanism-based sequencing. Clinical translation will depend on biomarker-guided patient selection, localized delivery and treatment sequencing that preserves antimicrobial defense and tissue homeostasis.