Neo-BCV induces macrophage-associated immunometabolic remodeling and anti-tumor immunity in solid tumors

Immunotherapy targeting the PD-1/PD-L1 axis has transformed cancer treatment; however, limited response rates and therapeutic resistance remain major challenges. Here, we developed a novel multi-component inactivated bacterial complex vaccine (Neo-BCV) to enhance anti-tumor efficacy by reprogramming innate immune responses. Neo-BCV significantly suppressed tumor growth without inducing systemic toxicity and remodeled the tumor immune microenvironment by promoting macrophage infiltration and polarization toward an M1-like phenotype while reducing M2-like TAMs. These changes were associated with enhanced CD8⁺ T-cell infiltration, effector memory phenotype, and cytokine production. Mechanistically, Neo-BCV activated NF-κB/NLRP3 signaling and induced metabolic and inflammatory reprogramming in macrophages. Macrophage depletion partially impaired Neo-BCV-mediated tumor control, indicating an important role for macrophages in the anti-tumor activity of Neo-BCV. Importantly, Neo-BCV demonstrated anti-tumor efficacy in additional MC38 and Hepa1-6 subcutaneous tumor models, accompanied by enhanced M1-like macrophage polarization and CD8⁺ T-cell infiltration. Furthermore, in a registered clinical study (ClinicalTrials.gov: NCT05747339; registered February 16, 2023) involving 27 patients with advanced solid tumors, Neo-BCV demonstrated a disease control rate of 77.78% with a favorable safety profile. Collectively, these findings demonstrate that Neo-BCV reshapes the tumor immune microenvironment through macrophage activation and enhances adaptive anti-tumor immunity. Its preclinical anti-tumor activity, together with a trend toward improved tumor control when combined with immune checkpoint blockade, and preliminary clinical activity support further evaluation of Neo-BCV as a potential immunotherapeutic strategy for solid tumors.