Open Access
REVIEW
Salmonella-Based Cancer Therapy: Strain-Dependent Immune Modulation, Tumor-Cell Responses, and Translational Challenges
Li-Hsien Wu1, Ming-Der Huang1, Che-Hsin Lee1,2,3,4,*
1 Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
2 Aerosol Science Research Center, National Sun Yat-sen University, Kaohsiung, Taiwan
3 Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
* Corresponding Author: Che-Hsin Lee. Email: 
(This article belongs to the Special Issue: Discovery of a Potent Antitumor Agent: Mechanistic Insights and Therapeutic Potential)
Oncology Research https://doi.org/10.32604/or.2026.086268
Received 27 May 2026; Accepted 07 September 2026; Published online 14 September 2026
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.
Keywords
Salmonella; tumor microenvironment (TME); immune modulation; cell death; translational safety
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