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.
Abstract
Immunotherapy has redefined oncology, yet its efficacy remains constrained by low response rates, primary or acquired resistance, immune-related toxicities, and escalating costs. Bacteria-mediated cancer immunotherapy (BCIT), which exploits the intratumoral microbiota as a programmable immunotherapeutic platform, has therefore emerged as a promising strategy. Although anecdotal links between infection and tumor regression were documented over four millennia ago, the molecular underpinnings of BCIT have only recently become accessible through synthetic biology, single-cell sequencing, and gnotobiotic modeling. Here we synthesize current knowledge on how intratumoral bacteria either enhance or suppress malignancy via genotoxicity, epigenetic reprogramming, metabolic competition, and modulation of the tumor-immune interface. We dissect cutting-edge engineering approaches—quorum-sensing circuits, thermo-inducible switches, molecular mimicry, and biohybrid microrobots, that convert commensal or attenuated pathogenic strains into precision delivery vehicles for cytokines, checkpoint inhibitors, and neoantigens. Finally, we critically evaluate translational bottlenecks (safety, pharmacokinetics, regulatory science, inter-patient heterogeneity) and propose an AI-guided, microbiome-integrated framework to accelerate clinical translation. This Review provides a conceptual framework for harnessing living therapeutics to convert immunologically “cold” tumors into “hot”, therapy-sensitive lesions, and discusses key directions for future microbiome-driven oncology trials.
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.
Arman H. Sharifi, Ngoc Hai Trieu Phong, Anjali Marek et al.· Molecular Biomedicine· 0 citations
This review synthesizes recent advances in pharmaco‐microbiomics, reframing cancer treatment in a hologenetic context, with host, tumor and microbiome acting as a tripartite entity. We comprehensively review microbiome‐mediated regulation of chemotherapeutic responses, encompassing both chemosensitization and resistance. At the molecular level, commensal microbiota enhance immunogenic cell death (ICD) and anti‐tumor immune responses, while intratumoral bacteria confer resistance through intracellular sequestration, induction of autophagy and drug inactivation (cytidine deaminase‐mediated gemcitabine degradation and β‐glucuronidase‐driven irinotecan toxicity). Our review also discusses systemic metabolic interactions including the “butyrate paradox”, competition for transporters, and microbiome‐mediated pharmacokinetics. Moving beyond microbiome profiling, we highlight functional metagenomics and resistome‐based patient stratification, complemented by AI‐based predictive modeling to predict non‐responders. In terms of translation, we outline next‐generation therapies such as engineered living medicines (ELMs), CRISPR‐bacteria for gene editing, precision bacteriophage therapy and postbiotic metabolites as precision approaches to reshape the tumor‐microbiome landscape. Finally, we present a clinical strategy combining microbiome companion diagnostics and co‐formulated “smart therapeutics” to combat multidrug resistance. This paradigm shift establishes microbiome as a predictor and therapeutic target in precision medicine.
Hailah M. Almohaimeed, Aniruddha Chatterjee, Sayani Ghosh et al.· Comprehensive Physiology· 0 citations
: 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.
Cancer immunotherapy has transformed the treatment landscape across multiple malignancies; however, durable responses remain limited to a subset of patients due to the emergence of intrinsic and acquired resistance. Increasing evidence suggests that therapeutic immune pressure itself acts as a selective force that shapes tumour evolution, driving the outgrowth of resistant clones. In this review, we synthesise current understanding of the molecular and cellular mechanisms underlying resistance to major immunotherapeutic modalities, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. We discuss tumour-intrinsic alterations such as defects in antigen presentation and immune signalling pathways, alongside tumour-extrinsic factors including immunosuppressive cell populations, metabolic constraints, and microbiome-mediated modulation. We further examine how these mechanisms converge within the tumour microenvironment to limit therapeutic efficacy. Emerging strategies to overcome resistance are highlighted, including rational combination therapies, next-generation engineered cellular platforms, and precision-guided approaches enabled by multi-omics profiling and artificial intelligence. Collectively, we propose that resistance should be understood as an adaptive consequence of therapeutic immune pressure. Building upon the principles of cancer immunoediting, we discuss how precision immune engineering, the rational design of personalised immunotherapeutic strategies informed by tumour biology, immune context, and predictive biomarkers, may be used to anticipate and overcome evolutionary escape mechanisms.
M. Anwer· International Immunopharmaco...· 0 citations
This critical narrative review evaluates tumour-targeting bacteria, engineered bacterial therapeutics, oncolytic viruses and manipulation of the host microbiome from a molecular-biology perspective.
Ummulkhairi Tukur, Imran Umar, Aminat Oyiza Musa et al.· Asian Journal of Research in...· 0 citations
Immune checkpoint blockade has redefined cancer therapy, yet durable responses remain constrained by resistance states that arise from coordinated tumor-cell, immune, stromal, vascular, lymphatic, and metabolic programs rather than from a single defective pathway. This review develops a translational framework in which tumor-intrinsic immune invisibility, myeloid and regulatory lymphocyte suppression, defective dendritic-cell priming, stromal and vascular exclusion, lymphatic control of antigen drainage, metabolic stress, and ILC2/type 2 immune plasticity are interpreted as interdependent ecosystem states. We discuss therapeutic strategies that reprogram these states, including myeloid and Treg modulation, stromal and vascular remodeling, preservation or restoration of productive lymphatic communication, cytokine and metabolic interventions, alternative checkpoint blockade, oncolytic viruses, vaccines, engineered cell therapies, and nanomedicine-enabled local delivery. Emphasis is placed on the lessons of failed or modestly effective trials, which show that biologically plausible interventions often fail when the dominant resistance bottleneck is not defined, tissue target engagement is not verified, or treatment sequence is not matched to the immune architecture of the tumor. We propose that future progress will depend on ecosystem-matched combinations guided by spatial biomarkers, on-treatment pharmacodynamics, and adaptive trial designs capable of linking mechanism to clinical decision-making.
