Abstract / Summary
Background: Tumor-associated macrophages (TAMs) function as central regulators bridging innate and adaptive immunity in the tumor microenvironment (TME). Therapeutic targeting of TAMs to promote M1 polarization represents a critical strategy for tumor suppression. Methods: Herein, we engineered a zinc metal-organic framework functionalized with mannose (MAN) and loaded with CLDN6 antigen (Zn-MAN@CLDN6). We systematically evaluated the anti-tumor efficacy and immunomodulatory functions of Zn-MAN@CLDN6 both in vitro and in vivo . The nanoplatform exhibited the potent cytotoxicity against lung cancer cells and enhanced the macrophage-mediated phagocytosis, while promoting M1 polarization and antigen presentation to activate T cells. Mechanistically, single-cell RNA sequencing (scRNA-seq) of tumor tissues elucidated the regulatory networks underlying its macrophage-targeted effects. Results: The vaccine targeted the highly expressed CD206 receptor on the surface of macrophages through surface modified mannose (MAN), achieving the selective endocytosis. Its acid responsive framework can rapidly degrade under acidic conditions of macrophage lysosomes, releasing Zn 2+ ions and the CLDN6 antigen. The released Zn 2+ acted as an endogenous adjuvant, driving macrophages towards M1 phenotype polarization and enhancing their antigen presentation ability (manifested as upregulation of CD86, MHC-I/II, and IL-12 expression). Meanwhile, macrophages that had undergone the re-education can present CLDN6 antigen to CD8 + T cells through a cross presentation mechanism, effectively activating specific cytotoxic T lymphocytes. In vitro and in vivo experiments had shown that the vaccine can significantly inhibit the growth and metastasis of CLDN6 + lung cancer cells. Research on the mechanism of action had shown that vaccines reshaped the tumor immune microenvironment, effectively recruiting (through CXCR6) and maintaining the survival and expansion of infiltrating CD8 + T cells by upregulating macrophages expression of CXCL16 and IL-15 through regulating the JAK3/STAT5 signal pathway. In addition, the vaccine demonstrated synergistic anti-tumor effects when combined with PD-1 immune checkpoint blockade therapy. The biosafety assessment showed that it had good biocompatibility. Conclusion: This study developed a nano vaccine platform that integrated targeted delivery, immune regulation, and specific anti-tumor response, providing a new strategy for immunotherapy of CLDN6 + lung cancer.