Postbiotics are genetically defined, non-viable microbial entities (such as heat-inactivated cells, lysed-cell fractions, and purified fermentation metabolites) that confer health benefits on the host¹. Unlike live probiotics, postbiotics resist gastric acid, are easily stored, and exhibit superior stability and safety profiles, while providing precisely quantifiable dose–response relationships and scalable, standardized manufacturing routes². Over the past decade, postbiotics have emerged as next-generation therapeutic ingredients in microbiome-based interventions; their molecular diversity underpins their immunostimulatory, gut-modulating, anti-inflammatory, and anti-tumor activities³. In oncology therapeutics, postbiotics, distinguished by an exceptional safety margin, multimodal synergistic mechanisms, and precise immunomodulation, have provided a transformative therapeutic paradigm. Postbiotic nanostructures are natural, self-assembled targeting platforms built around bacterial membrane vesicles and metabolite supramolecular assemblies. This review synthesizes current mechanistic insights, as well as pre-clinical and clinical advances in postbiotic-based anti-cancer strategies, to provide a comprehensive framework for the rational development and clinical deployment of postbiotic anti-tumor therapeutics.

Postbiotics can be taxonomically classified according to their mode of biogenesis, into metabiotics and paraprobiotics, both of which have a pleiotropic range of bioactivities⁴. The modes of postbiotic biogenesis are illustrated in Figure 1, and the characteristics of postbiotics are summarized in Table 1.

The specialized barrier architecture of malignant neoplasms prevents efficient drug delivery to neoplastic cells^18,19, whereas the immunosuppressive milieu of the tumor microenvironment (TME) restricts infiltration by inflammatory and immune effector cells. This limitation decreases the efficacy of immunotherapeutic modalities²⁰. As successors to probiotics, postbiotics directly regulate oncogenic signaling pathways, remodel the TME, and enhance antitumor immunity, while simultaneously reprogramming tumor metabolism. At a deeper level, postbiotic nanostructures, such as bacterial OMVs and metabolite-assembled nanoparticles, constitute the fundamental material basis for antitumor activity. These naturally derived nanocarriers exhibit inherent tumor tropism and exceptional biocompatibility, thereby enabling intelligent, site-specific drug delivery to neoplastic lesions. When used as adjuncts to existing antineoplastic regimens, they provide synergistic efficacy benefits and mitigate treatment-related toxicities (Figure 2).

The mechanisms of postbiotics in anti-tumor therapy have been increasingly clarified in terms of signaling pathway regulation, immune regulation, and metabolic intervention. The production process has become more precise and standardized, including extraction, purification, activity stability, and quality control. Basic research and translational application systems in this field have progressively improved as research has advanced and matured.

Postbiotic formulation MS-20 is a multi-strain metabolite consortium derived from probiotic bacteria and yeasts. When co-administered with an anti-PD-1, MS-20 increases gut microbial diversity, promotes effector CD8⁺ T-cell expansion, and downregulates PD-1 expression, thereby reconfiguring the TME. In mouse xenograft models, this combination elicits significant growth inhibition of colorectal and lung tumours³⁷. Notably, MS-20 is the first postbiotic preparation to receive U.S. FDA Generally Recognized as Safe status for oral use as an adjunct cancer therapy. It is compatible with standard-of-care agents, thereby offering a safe and effective option for patients¹³. Phase III trials evaluating MS-20 as an adjuvant treatment for non-small cell lung carcinoma (NSCLC) are currently underway³⁸. The study enrolled patients diagnosed with unresectable stage IIIB–IV metastatic NSCLC, including those with metastatic non-squamous carcinoma with wild-type EGFR/ALK/ROS1 genes, as well as patients with squamous cell carcinoma with wild-type EGFR/ALK genes. Eligible participants received an oral solution of the study drug at a dose of 4 c.c. twice daily for 48 weeks, and treatment efficacy was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). The objective response rate was defined as the proportion of patients achieving a predefined decrease in tumor size sustained for a minimum duration, encompassing both complete response and partial response. The MS-20–Keytruda combination group achieved an objective response rate of 75%, a value three times the 25% observed in the Keytruda monotherapy group. Moreover, the median progression-free survival was extended from 4.5 months in the control group to more than 12 months in the MS-20 group. A complete response was observed in 12.5% of patients receiving the combination therapy. These results support the potential of MS-20 to modulate the gut microbiome and enhance the clinical efficacy of Keytruda in advanced NSCLC. Orally administered Clostridium butyricum cells display surface-expressed SecD, which specifically binds the tumor-restricted receptor GRP78 on colorectal cancer cells. This binding inhibits downstream PI3K/Akt−NF-κB signaling, thus decreasing the secretion of the immunosuppressive cytokine IL-6 and alleviating CD8⁺ T cell inhibition. Consequently, enhanced T-cell receptor signaling, as indicated by increased phosphorylation of LCK/ZAP70, leads CD8⁺ T cells to release effector molecules (IFN-γ, TNF-α, and granzyme B). Simultaneously, tumor-associated macrophages are prevented from adopting the immunosuppressive M2 phenotype. Collectively, these effects remodel the tumor immune microenvironment and offer a clinically translatable approach to address resistance to immune-checkpoint blockade in microsatellite-stable colorectal cancer³⁹. Sudheer et al. have demonstrated that the postbiotic 2,4-di-tert-butylphenol, a bioactive small-molecule metabolite produced by Lactobacillus plantarum, disrupts carbohydrate metabolism and induces a metabolic shift toward lactose utilization, while simultaneously engaging the oral-squamous-cell-carcinoma-associated signaling proteins p38 and NF-κB²². To accelerate clinical translation, researchers should delineate specific protein–protein interaction networks and core molecular mechanisms of postbiotics, to establish a foundation for the precise prediction and screening of highly effective therapeutic candidates. In addition, innovative targeted delivery technologies should be developed to expand the multitarget synergistic network of postbiotics in combination with radiotherapy, targeted therapy, and engineered bacterial therapy. Large-scale clinical investigations in diverse cancer types including breast and lung cancers should also be promoted to strengthen the evidence base with high-quality clinical data. Furthermore, individualized therapeutic regimens for postbiotics should be optimized, and standardized efficacy evaluation systems should be established.

Postbiotics have progressed to industrial-scale production as complementary agents in cancer treatment. A postbiotic nutritional solution has been found to counteract cyclophosphamide-induced myelosuppression, thereby promoting strong recovery of white blood cell and platelet counts after chemotherapy, and decreasing irinotecan-associated diarrhea by 60%. Mechanistically, the formulation enhances intestinal barrier function by increasing the expression of the tight junction proteins ZO-1 and occludin. This supportive therapy consequently decreases both immunosuppression and gastrointestinal toxicity. Similarly, the same group has developed a multi-strain Bifidobacterium longum preparation that effectively inhibits the growth of the mouse hepatocellular carcinoma line H22. When combined with botanical compounds from Astragalus mongholicus and Polygonatum sibiricum, it lessens tumor-related inflammatory responses⁴⁰.

Although several postbiotic formulations have entered clinical trials, and a subset have received regulatory approval as adjuvant therapeutics, their large-scale industrial manufacture faces many obstacles. At the process level, current inactivation protocols remain suboptimal: thermal inactivation frequently degrades functional moieties, thus resulting in fluctuating lot-to-lot potency. Stabilization technologies are equally limited: spray-drying, for example, retains only 68%–72% of the initial bioactivity and compromises storage stability. In quality control, the substantial variability (as much as ±35%) in vitro immunostimulation assays highlights the lack of a standardized framework for potency assessment and hinders meaningful cross-batch comparability. Another challenge is determining appropriate dosages for postbiotics. The dose-response relationship for inactivated lactic acid bacteria often follows a biphasic, U-shaped curve, wherein bioactivity is absent at low doses and suppressed at high doses, thereby posing substantial challenges in defining a safe and effective therapeutic window⁴¹.

Postbiotics are non-viable cellular fractions and metabolites derived from probiotic organisms. Both types of postbiotics specifically target oncogenic signaling pathways and consequently exert tumor-suppressive effects, while simultaneously regulating the immune microenvironment and enhancing the effectiveness of anti-tumor immunity. Additionally, postbiotics reprogram tumor metabolism and, when used as adjunctive therapies alongside existing cancer treatments, improve therapeutic outcomes and decrease treatment-related toxicities. Their chemically diverse and bioactive profiles enable multiple synergistic anticancer mechanisms.

Although postbiotics’ established safety profiles and the ability for scale-up with standardized manufacturing provide a foundation for translation, their clinical applications remain limited by several major challenges. Postbiotic is a loosely defined term, and products from different taxa or manufacturing processes exhibit markedly differing bioactivities. No quality control framework is currently universally accepted. Advancing mechanistic understanding of probiotic activity is driving the diversification of the quality standard framework for postbiotic formulations. For example, paraprobiotic preparations composed primarily of intact, heat-inactivated probiotics can be quality-controlled through well-defined physicochemical metrics, such as the numerical count of microbial bodies and culture pH. Metabiotics comprising secreted metabolites are monitored by targeted identification and quantification of bioactive moieties such as short-chain fatty acids and bacteriocins. Omics platforms now furnish high-resolution routes for postbiotic taxonomic authentication and quality framework construction: metabolomics comprehensively maps the secreted metabolite landscape, proteomics defines the proteinaceous signature of para-probiotic biomass, and genomics provides unambiguous taxonomic authentication plus early exclusion of virulence or antimicrobial-resistance determinants, thereby enabling the establishment of rigorous quality specifications. Additionally, the therapeutic effectiveness of postbiotics depends on host microbiota composition, genetic background, and tumor type, and substantial variability is observed among individuals. To address this challenge, integrating patient tumor genomic profiles with genomic fingerprints of postbiotic strains would enable precise estimation of host strain compatibility, thereby providing a rational basis for personalized regimen design and enhancing therapeutic precision and efficacy. Similarly, because mechanistic understanding of the anti-tumor effects of postbiotics has come primarily from animal studies, their targeting efficiency in humans and long-term safety remain to be addressed. Moreover, only few postbiotics have advanced to clinical trials, most of which have been limited by small sample sizes and have lacked randomized controlled designs. The optimal administration method, considering dose and timing for adjuvant therapy, remains to be determined.

Given their polypharmacological anti-tumor mechanisms and favorable safety margins, postbiotics are a valuable therapeutic approach. Future directions should include: (i) synthetic-biological consortia that combine probiotics and prebiotics to increase postbiotic bioavailability; (ii) development of precision-medicine algorithms that incorporate microbiota profiling to identify responders and provide personalized supplementation of the specific postbiotic components each needs; and (iii) engineered delivery platforms in which synthetic-biology circuits control tumor-microenvironment-responsive release, thereby enhancing on-target effectiveness.