Trained immunity in cancer immunotherapy and vaccine development: mechanisms, evidence gaps, and translational opportunities.

Breakthroughs in cancer immunotherapy have been overwhelmingly driven by advances in adaptive immunity, leaving the therapeutic potential of innate immunity largely untapped, a gap in the current treatment paradigm. Trained immunity, defined by the durable, mitotically maintained metabolic and epigenetic memory that innate immune cells acquire after transient stimulation, offers a new approach to addressing this deficit. Here we survey the triggering signals, cellular heterogeneity, and molecular circuitry that govern trained immunity within the tumor microenvironment. We dissect its dualistic character: the mechanistic basis by which trained immunity can either restrain or promote tumor progression, and what this ambivalence means for the design of next-generation immunotherapies. These insights inform a growing pipeline of trained-immunity-based cancer vaccines, which we categorize into four engineered platforms, recombinant BCG, β-glucan nanoformulations, lipid nanoparticle (LNP)-mRNA bifunctional vaccines, and commensal-derived adjuvants. We further propose that vaccine efficacy may depend in part on host immune context, and outline stratification strategies and dosing schedules that may need to be adjusted according to individual immune status, pending clinical validation. In aggregate, evidence from human bladder cancer, preclinical tumor models, and non-tumor trained immunity studies suggests that trained immunity could elevate innate immunity from a supporting role toward an independent therapeutic axis, although most of its direct cancer applications remain at the preclinical or conceptual stage.