Targeting intratumoral bacteria reverses MHC-I suppression and enhances nano-based chemoimmunotherapy in colorectal cancer.

Abstract

Background: Emerging evidence indicates that diverse bacteria colonize tumors and facilitate oncogenesis through multifaceted mechanisms, predominantly through immunosuppression of the tumor microenvironment (TME). Fusobacterium nucleatum (F.n) exemplifies this phenomenon in colorectal cancer (CRC), where it mediates immune evasion via tumor cell autophagy and upregulation of programmed death-ligand 1 (PD-L1). Effective strategies for combining precise elimination of intratumoral F.n with chemotherapy remain lacking.

Methods: A targeted multimodal nano-based chemoimmunotherapy was engineered by co-loading hyaluronic acid (HA)-coated silver nanoparticles (Ag NPs) and paclitaxel (PTX) into tumor-targeting cationic liposomes (Cls). The combination was mechanistically evaluated for F.n eradication capacity, antitumor effects, and remodeling of the tumor immune microenvironment. Antitumor efficacy and safety were also evaluated in vivo using a tumor-bearing mouse model.

Results: Intratumoral F.n subverted antitumor immunity through a dual mechanism, coupling major histocompatibility complex class I (MHC-I) degradation with PD-L1 upregulation. HA@Ag NPs/PTX Cls exerted synergistic antitumor effects through multimodal mechanisms. HA@Ag NPs/PTX Cls eliminated intratumoral bacteria, restoring microbial homeostasis, enhancing MHC-I antigen presentation, increasing production of tumor necrosis factor (TNF) and interferon (IFN), and downregulating PD-L1 to promote tumor immunorecognition. Combined with PTX-induced apoptosis, the nanotherapy inhibited both primary and metastatic tumors. Notably, bacterial clearance-triggered immune activation established long-term immunological memory, providing durable protection against tumor recurrence. These results highlighted the dual benefit of liposomes in addressing microbial dysbiosis and immune evasion in CRC.

Conclusion: This innovative liposomal strategy disrupts the immunosuppressive TME and synergizes with a small-molecule chemotherapeutic agent to induce tumor cell apoptosis, representing a novel approach to potentiate cancer immunotherapy.