Salmonella-Based Cancer Therapy: Strain-Dependent Immune Modulation, Tumor-Cell Responses, and Translational Challenges

Abstract

: Cancer remains a major global health and socioeconomic burden. Although advances in surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have substantially improved clinical outcomes, conventional treatment strategies still face major limitations, particularly for tumors with hypoxia, metastasis, recurrence, immune suppression, and drug resistance. Attenuated or engineered Salmonella strains have emerged as promising biological agents because of their preferential tumor accumulation in preclinical models, immunostimulatory activity, and genetic tractability. This review aims to summarize the multifaceted mechanisms by which Salmonella reshapes the tumor microenvironment (TME) and promotes antitumor responses, and to evaluate the major challenges to clinical translation. Salmonella -based therapy can enhance T-cell activation, modulate immune checkpoint pathways, reprogram tumor-associated macrophages, and modulate neutrophil recruitment. Defined strains and engineered platforms have also been associated with autophagy, apoptosis, localized necrosis, inflammasome-associated pyroptosis, and, in selected models, ferroptosis. Selected preclinical studies suggest effects on nutrient availability, hypoxia-associated signaling, drug efflux, and treatment sensitivity; however, these observations do not establish a general program of Salmonella -driven metabolic reprogramming or therapeutic-resistance reversal. Despite encouraging preclinical evidence, the clinical translation remains limited by host immune clearance, systemic safety concerns, inconsistent intratumoral colonization, and insufficient therapeutic control. Future research should focus on optimized strain engineering, controllable safety-switch systems, improved tumor-colonization strategies, and rational combinations with chemotherapy, targeted therapy, or immune checkpoint blockade. Overall, the efficacy and safety of Salmonella -based cancer therapy are shaped by bacterial design, tumor biology, host immunity, and treatment regimen.