Toward a Dual-Axis Model of Microbiome Modulation in Cancer Immunotherapy: Pathobiont Elimination and Functional...

The gut microbiome is increasingly recognized as a modulator of cancer immunotherapy efficacy, including responses to immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy. Recent clinical trials of microbiome-targeted interventions such as fecal microbiome transplantation (FMT) and live biotherapeutic products (LBPs) suggest the potential to enhance antitumor immunity and improve clinical outcomes. Yet responses remain heterogeneous and are not fully explained by engraftment of donor taxa alone.

We integrate evidence from interventional trials, observational cohort studies, and principles from gut microbial ecology to develop a model hypothesis on how microbiome-targeted therapies may shape response to immunotherapy, with potential to inform future trial design, analyses, and interpretation.

Drawing on the available evidence, we propose that therapeutic perturbation of the gut microbiome may augment immunotherapy efficacy through two parallel axes: (1) elimination of immunosuppressive pathobionts that restrain CD8+ T-cell activation and promote myeloid-mediated immunosuppression, and (2) functional restoration of the gut ecosystem through engraftment of taxa that provide metabolites, structural cues, and immunoregulatory signals required for effective antitumor immunity. The success of both axes appears to depend on ecological processes governed by predator-prey dynamics, including colonization resistance, resilience of the resident microbiota, and the ability of administered organisms to displace entrenched dysbiotic communities. This ecological lens may help to explain discrepancies across trial designs, donor types, and intervention modalities, and suggests that complete donor engraftment is neither necessary nor sufficient for clinical benefit.

A dual-mechanism model of pathobiont elimination and functional microbial restoration may help explain microbiome-mediated enhancement of cancer immunotherapy, highlighting a balanced immune permissive gut ecosystem as a key determinant of therapeutic success.