Attenuated Salmonella as a modulator of the cancer-immunity cycle: from innate activation to adaptive antitumor...

Attenuated engineered strains of Salmonella have emerged as promising tools in cancer immunotherapy due to their intrinsic tumor-targeting properties and their ability to reshape the tumor immune microenvironment. Beyond their direct cytotoxic effects on tumor cells, Salmonella profoundly modulates both innate and adaptive immune responses, impacting multiple steps of the cancer-immunity cycle. In this review, we discuss how attenuated Salmonella induces immunogenic tumor cell death, promotes antigen release and cross-presentation, enhances lymphocyte activation, and facilitates immune cell infiltration into the tumor microenvironment. We also address its role in controlling metastatic disease and the induction of long-term adaptive immune memory. Furthermore, we highlight unresolved questions regarding the contribution of immune activation, tolerance, and trained immunity, which may underlie the transient nature of antitumor effects observed in some models. Finally, we examine the translational hurdles that have limited clinical efficacy-such as the balance between attenuation and potency, endotoxin tolerance, and preexisting immunity-and outline emerging engineering strategies to overcome them. Understanding these mechanisms is essential for optimizing Salmonella-based strategies and their integration with current immunotherapies.