Current evidence supports bacteria as a promising precision modality, particularly for immunologically “cold” or hypoxic tumors; however, major challenges remain in the predictability of intratumoral distribution, host clearance, genetic stability, and long-term safety.
Abstract
Targeted cancer therapies increasingly require platforms that can penetrate poorly perfused tumor regions while minimizing systemic toxicity. Bacteria, owing to their intrinsic tumor tropism, genetic programmability, and immunostimulatory properties, have re-emerged as versatile anticancer agents, ranging from attenuated tumor-colonizing strains to highly engineered “living therapeutics.” In this review, we synthesize the mechanistic foundations and therapeutic advances of bacterial-based cancer therapy through four major themes. First, we examine foundational mechanisms, including tumor-selective colonization, direct oncolysis and cytotoxicity, activation of innate and adaptive immunity, and remodeling of the tumor microenvironment. Second, we discuss engineering strategies that enable controllable delivery of therapeutic payloads, such as cytokines, antibodies and nanobodies, enzyme-prodrug systems, toxins, and nucleic-acid therapeutics, while also improving biosafety and biocontainment. Third, we evaluate combination strategies integrating bacteria with chemotherapy, radiotherapy, phototherapy, and immunotherapy, with emphasis on how bacteria complement conventional modalities by targeting hypoxic, necrotic, and immunologically refractory tumor niches. Fourth, we summarize translational progress, including representative early-phase clinical experiences, manufacturing challenges, and major safety constraints. We also highlight emerging microbiome-disease databases and computational resources that may support target selection, biomarker discovery, and therapy-response stratification. Current evidence supports bacteria as a promising precision modality, particularly for immunologically “cold” or hypoxic tumors; however, major challenges remain in the predictability of intratumoral distribution, host clearance, genetic stability, and long-term safety. Addressing these barriers through rigorous engineering, standardized manufacturing, and clinically meaningful endpoints will be essential for the next generation of bacterial therapeutics in oncology.
: 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.
Abstract Cancer poses an escalating threat to global public health, characterized by continuous rises in both incidence and mortality. While conventional tumor interventions including surgery, chemotherapy and radiotherapy have made considerable progress, their clinical efficacy is severely constrained by systemic toxic side effects, inadequate targeting precision and frequent severe postoperative and treatment-related sequelae. Nanodrug delivery systems have evolved as a viable therapeutic alternative to optimize tumor targeting and minimize systemic toxicity. However, conventional nanocarriers suffer from rapid clearance by the mononuclear phagocyte system, and the intricate, heterogeneous tumor microenvironment (TME) further impairs effective intratumoral drug penetration and uniform distribution. As an emerging class of living delivery vectors, probiotics have recently gained extensive research attention by virtue of their intrinsic tumor tropism, unique capacity to adapt to and remodel the TME, and excellent synergistic compatibility with multiple therapeutic regimens. This review systematically elaborates the biological mechanisms governing the tumor-targeted accumulation and TME-responsive properties of probiotics, summarizes core strategies for probiotic genetic modification and hybrid system construction, and compares the strengths and applicable scenarios of diverse probiotic chassis strains. We further discuss the synergistic potential of probiotic-based platforms combined with immunotherapy, chemotherapy, radiotherapy and physical therapy. Finally, this article underscores the key bottlenecks and future research directions for the clinical translation of probiotic-based antitumor therapeutics, aiming to provide rigorous theoretical support for their broader clinical application in cancer treatment.
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The integration of engineered microorganisms and nanomaterials represents a promising strategy for next-generation precision oncology and may accelerate the development of more effective and personalized cancer therapies.
A conceptual framework for harnessing living therapeutics to convert immunologically “cold” tumors into “hot”, therapy-sensitive lesions is provided and an AI-guided, microbiome-integrated framework to accelerate clinical translation is proposed.
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A translational framework for overcoming key barriers in pharmaceutical intervention design for oncology applications is outlined, integrating drug delivery engineering, molecular biopharmaceutics, and computational optimization.
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