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Background Microsatellite stable (MSS) colorectal cancer (CRC) exhibits primary resistance to immunotherapy with response rates below 5%. This study aimed to elucidate the molecular mechanisms by which Akkermansia muciniphila (Akk) remodels the tumor immune microenvironment and evaluate its clinical value in combination with anti-PD-1 therapy for advanced MSS CRC.Methods Preclinical studies used CT26 mouse models (MSS CRC) with oral Akk administration to assess tumor growth effects. Tumor immune microenvironment changes were analyzed via single-cell RNA sequencing (scRNA-seq) and flow cytometry. Clinical studies employed qPCR and fluorescence in situ hybridization (FISH) to detect Akk abundance in fecal and tumor tissues of MSS CRC patients before immunotherapy, assessing its predictive value for treatment response. A single-arm phase I trial ( NCT06865521) enrolled 20 patients with treatment-refractory advanced MSS CRC who received oral Akk probiotic capsules combined with PD-1 inhibitors, evaluating safety (CTCAE 5.0), preliminary efficacy (RECIST v1.1), and systemic immune profile dynamics.Results In animal models, Akk suppressed macrophage efferocytosis via TLR2/NF-κB signaling, activating the cGAS-STING pathway and subsequent IFN-β release. This significantly enhanced tumor-infiltrating CD8 + T cell effector function, suppressing CRC progression and improving PD-1 inhibitor efficacy. Clinical cohort analysis showed that MSS CRC patients with higher Akk abundance showed better clinical responses to immunotherapy. The phase I trial (N=20) demonstrated favorable safety: 70% (14/20) experienced grade 1-2 immune-related adverse events, 10% (2/20) had grade 3 events, with no grade 4 events or treatment-related deaths. The objective response rate (ORR) was 20% (1 CR + 3 PR). Immune monitoring revealed significant peripheral immune activation in responders: increased effector CD8+ T cell proportions, elevated serum IFN-γ and TNF-α levels.Conclusions This study systematically elucidates the molecular mechanisms by which Akk reverses the immunosuppressive microenvironment in MSS CRC. Clinical findings suggest Akk levels may predict treatment response. The phase I trial confirms the safety and clinical feasibility of Akk-PD-1 inhibitor combination therapy, providing a novel strategy to overcome immunotherapy resistance in advanced MSS CRC and establishing a foundation for further randomized controlled trials.Trial Registration NCT06865521Ethics Approval The clinical trial was conducted at West China Hospital of Sichuan University and registered on ClinicalTrials.gov (registration number: NCT06865521).All patients were recruited and treated at West China Hospital of Sichuan University, where the study protocol was approved by the Institutional Review Board in accordance with the Declaration of Helsinki. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and applicable local regulations. Written informed consent was obtained from all participants, who retained the right to withdraw at any time without affecting their standard treatment for advanced MSS CRC.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.