The benefits and pitfalls of trained immunity in listeria monocytogenes-based cancer vaccination: how host innate-cell reprogramming may amplify, distort, or constrain the therapeutic potential of live bacterial vectors

Live recombinant Listeria monocytogenes (Lm) vaccines are usually framed as intracellular antigen-delivery platforms endowed with intrinsic adjuvant activity. Here we argue that this view may be incomplete. Because Lm vaccines strongly engage innate immune cells, their efficacy might depend on both immediate inflammatory signaling and a separately established or acquired trained state. Importantly, direct evidence that recombinant Lm induces bona fide trained immunity - defined by durable functional changes supported by epigenetic and metabolic reprogramming beyond the initial inflammatory phase - is currently limited. We consider two distinct questions: whether pre-existing trained immunity changes the efficacy of subsequent Lm vaccination, and whether Lm vaccination itself induces a lasting trained innate program in addition to antigen-specific CD8 T-cell immunity. Pre-existing training could alter vector clearance, antigen presentation, and initial T-cell priming, whereas hypothetical Lm-induced training could affect later tumor-microenvironment function, memory recall, and long-term tumor control without accounting for the initial CD8 T-cell response. Either scenario might enhance or constrain efficacy, and the two require different experimental examinations. We propose trained innate reprogramming as a testable mechanistic variable, rather than an established property of Lm vaccines, with implications for vaccine design, repeated dosing, safety, and interpretation of antitumor vaccines.