Microbes trigger cell death to boost cancer immunotherapy effectiveness

Traditional cancer treatments like chemotherapy and radiotherapy can induce immunogenic cell death (ICD), but their efficacy is often limited by drug resistance, severe off-target toxicity, and immune-related adverse events. Furthermore, the immunosuppressive tumor microenvironment frequently dampens these therapies' ability to spark a durable, body-wide immune response. Consequently, many tumors remain "cold" and unresponsive to advanced immunotherapies including immune checkpoint inhibitors (ICIs). The gut microbiota contributes to cancer pathogenesis and therapeutic modulation through chronic inflammation, direct DNA damage, and metabolite-mediated signaling pathways such as Wnt/β-catenin and nuclear factor-κB. Based on these challenges, an in-depth investigation into novel, biocompatible agents that can safely and efficiently trigger ICD, such as the body's own microbiota, is urgently needed.

Researchers from the Cancer Hospital of China Medical University and Liaoning Cancer Hospital & Institute in Shenyang, China, have published (DOI: 10.20892/j.issn.2095-3941.2025.0769)a comprehensive review on this topic. The study appears in the May 2026 issue of Cancer Biology & Medicine. The team details how bacteria, viruses, fungi, and their metabolic byproducts can induce ICD. Their work shows that these microbial agents remodel the tumor microenvironment (TME) and activate long-term systemic antitumor immunity, presenting a promising new frontier for combination cancer therapies.

The review highlights multiple mechanisms by which microbes induce ICD. Infection with Pseudomonas aeruginosa triggers tumor cell necroptosis via phosphorylation of receptor-interacting protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL), coupled with high mobility group box 1 (HMGB1) release—hallmark features of ICD. Similarly, infection of melanoma cells with Salmonella typhimurium causes cytoplasmic vacuolization and elevated extracellular adenosine triphosphate (ATP) release, enabling efficient phagocytosis by antigen-presenting cells (APCs). Among probiotics, Lacticaseibacillus casei ATCC 393 treatment upregulates death receptors FS7-associated cell surface antigen and death receptor 4/5 while promoting calreticulin (CRT) surface exposure and HMGB1 nuclear translocation. Beyond whole bacteria, fungal metabolites are potent inducers. A compound from Aspergillus ustus called MHO7 triggers reactive oxygen species (ROS) production and activates the protein kinase R-like ER kinase/eukaryotic initiation factor 2 alpha/activating transcription factor 4/C/EBP homologous protein (PERK/eIF2α/ATF4/CHOP) pathway, forcing triple-negative breast cancer cells to release DAMPs and recruit CD4+ and CD8+ T cells while decreasing regulatory T (Treg) cells. The review also explores how short-chain fatty acids (SCFAs), produced by beneficial gut bacteria like Faecalibacterium, enhance CD8+ T cell cytotoxicity via the G protein-coupled receptor 109A/homeodomain only protein homeobox signaling pathway.

"The beauty of this approach is that it turns a basic biological process—cell death—into a powerful alarm signal for the immune system," the authors explained. "We're not just killing tumor cells; we're using microbes to fundamentally change how the body perceives and attacks them. By reprogramming the tumor microenvironment, we can potentially convert a patient's own gut bacteria into powerful allies against cancer. This isn't about simply adding another drug; it's about rewiring the existing relationship between the microbiome and the immune system to create a durable, personalized anti-tumor response. The microbiota offers unique advantages, including inherent adjuvanticity and tumor-targeting specificity."

This research opens several therapeutic avenues. Engineered bacterial strains, such as attenuated Salmonella VNP20009 and Bifidobacterium spp., can serve as highly efficient drug delivery vectors that specifically accumulate in hypoxic tumors when combined with nanomaterials loaded with photothermal agents and chemotherapeutic drugs. A strategic combination of probiotics with standard chemotherapy or ICIs could synergistically boost treatment efficacy. Furthermore, simple dietary interventions, such as increasing fiber intake to produce antitumor SCFAs, offer a supportive strategy to modulate the gut microbiota and enhance ICD. The implications for patients are profound, particularly for those resistant to current immunotherapies. By transforming "cold" tumors into "hot" ones, these microbial-based strategies could make immunotherapy effective for a much larger population, turning the tide against hard-to-treat cancers including pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer.

Source:

Chinese Academy of Sciences

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