An all-in-one polymeric nanomedicine as in situ cascade cancer vaccine for potent cancer immunotherapy

Abstract

Cancer vaccines that exploit tumor antigens to induce specific immune responses hold great promise for cancer treatment, with several products already approved. However, limitations such as the lack of tumor-specific antigens, inadequate antigen processing by antigen-presenting cells (APCs), and the suppressive tumor microenvironment significantly hinder their therapeutic efficacy. In this study, we present a cascade cancer vaccine, PAEMA-PC_R848, designed for efficient in situ vaccination against cancer in an “all in one” manner. PAEMA-PC_R848 rapidly disintegrates in response to the acidic tumor microenvironment, triggering protonation of its core and subsequent release of PEG-modified photosensitizer (PEG-Ce6), poly(2-azepane ethyl methacrylate) (PAEMA), and the immune adjuvant resiquimod (R848), which together elicit a cascade anticancer immune response. The PEG-Ce6 integrates into the phospholipid bilayer of tumor cell membranes, facilitating the release of endogenous tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Meanwhile, PAEMA, R848, and the released TAAs migrate to lymph nodes, where they promote the maturation of APCs and the generation of antigen-specific CD8⁺ T cells. Additionally, R848 promotes M1 polarization of macrophages within the tumor microenvironment, enhancing tumor cell engulfment and modulating immune suppression. Notably, this cascade nanovaccine resulted in the complete eradication of distant tumors in some mice and induced long-term immune memory, providing potent protection against tumor recurrence and metastasis.