Abstract

Tumor‐associated macrophages (TAMs) are abundant in tumor microenvironment (TME) but fail to act as vaccine targets due to their inferior immune response. Here, a robust strategy was presented to develop potent cancer vaccines toward TAMs via a multi‐functional adjuvant, breaking through the conventional vaccine design centered on dendritic cells (DCs). To address this issue, rigidity‐tunable nanovesicles (P‐P m ) were engineered by surface decoration of Chol‐PItEG m with precise regulation of chain lengths. The P‐P m nanovesicle exerted mechanically induced adjuvanticity through not only enhancing endocytosis in a rigidity‐dependent manner to facilitate antigen delivery and processing in TAMs, but also activating the mechanosensitive Piezo1/YAP/TAZ signaling pathway to promote M2‐like TAMs reprogramming. Furthermore, the rigid P‐P m nanovesicle could efficiently co‐encapsulate antigenic gp100 peptide and toll‐like receptor agonist resiquimod (R848) to form an anti‐melanoma vaccine P@Rg‐P m . After intravenously injected, CD8 + T cell infiltration was increased while immune‐suppressive cell level of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) were decreased along with elevated levels of proinflammatory factors including IL‐1β, IFN‐γ, and IL‐12, demonstrating the effective reversal of immunosuppressive TME. Consequently, P@Rg‐P m demonstrates significant antitumor efficacy against B16‐F10 melanoma in both therapeutic and prophylactic models without any assistance of other therapies. Rigidity‐tunable nanovesicle (P‐P m ) with mechanically induced adjuvanticity toward tumor‐associated macrophages (TAMs) was designed to engineer R848/gp100 antigen ‐loaded nanovaccine (P@Rg‐P m ), which achieved outstanding anti‐tumor outcomes in both therapeutic and preventive model of B16‐F10 melanoma.