image: Microbiota and microbial metabolites initiate antitumor immune responses by inducing ICD. This schematic systematically illustrates the complete process by which microbiota and microbial metabolites, serving as inducers of ICD, ultimately initiate specific antitumor immune responses through a cascade of “ICD induction–DAMPs release–DAMPs recognition–DC maturation–antigen presentation–T cell activation and tumor killing.” 1. ICD induction: Microbiota and microbial metabolites act on tumor cells as inducers of ICD, triggering ICD in tumor cells. 2. DAMPs release: Dying tumor cells undergoing ICD release or expose various DAMPs, including ATP, HMGB1, and HSPs, as well as the translocation of CRT from the ER to the cell surface. 3. DAMPs recognition: The released DAMPs are recognized and taken up by immature DCs and these DAMPs initiate the activation program of the DCs. 4. DC maturation: Stimulated by DAMPs, immature DCs differentiate into mature DCs. This transition equips DCs with a highly efficient antigen-presenting capacity. 5. Antigen presentation: Mature DCs present tumor antigens via MHC molecules on the surface to the TCRs on CD8+ T cells, thereby establishing a bridge for antigen-specific recognition. 6. T cell activation and tumor killing: CD8+ T cells that recognize the antigen–MHC complex are activated, initiating a specific antitumor immune response. These activated CD8+ T cells (effector T cells) can precisely recognize and kill tumor cells. ATP, adenosine triphosphate; CRT, calreticulin; DAMPs, damage-associated molecular patterns; DC, dendritic cell; ER, endoplasmic reticulum; HMGB1, high mobility group box 1; HSPs, heat shock proteins; ICD, immunogenic cell death; MHC, major histocompatibility complex; TCR, T cell receptor.
Credit: Cancer Biology & Medicine
A new study reveals that microbiota and their metabolites can effectively reprogram immunogenic cell death (ICD), a unique form of cell death that activates the body‘s immune system against tumors. This process transforms immunologically “cold,” therapy-resistant tumors into “hot,” responsive ones by triggering the release of key danger signals known as damage-associated molecular patterns (DAMPs). These signals activate antigen-presenting cells and cytotoxic T cells, generating long-lasting systemic antitumor immunity. The findings offer a powerful new strategy to overcome the limitations of traditional cancer therapies, potentially leading to more effective and personalized treatments that harness the body’s own microbial inhabitants to fight cancer.
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.
###
References
DOI
10.20892/j.issn.2095-3941.2025.0769
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0769
Funding Information
The National Natural Science Foundation of China (Grant No. 82373113, XJ), Natural Science Foundation of Liaoning Province (Grant No. 2025-MSLH-421, XJ), LiaoNing Revitalization Talents Program (Grant No. XLYC1907160, XJ), Shenyang Breast Cancer Clinical Medical Research Center (Grant No. 2020-48-3-1, ST), and Shenyang Public Health R&D Special Project (Grant No. 22-321-31-04, ST).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).
Journal
Cancer Biology & Medicine
Subject of Research
Not applicable
Article Title
Microbial reprogramming of immunogenic cell death: a new paradigm in tumor immunotherapy
Article Publication Date
20-May-2026
COI Statement
The authors declare that they have no competing interests.