Immunotherapy of cold tumors via full-course ICD activation by nanotherapeutics-based cascade precise tumor killing and efferocytosis inhibition

Dual-protein co-delivery nanocarriers enabling full-course ICD through to antigen presentation • A tumor-targeted nanoplatform (P/A@MnO₂-M) was developed to achieve full-course ICD activation, from tumor-specific ICD induction via PPE to efferocytosis blockade via Annexin A5. This strategy bridges cell death induction, DAMPs release, and antigen presentation, addressing the challenge of transient signals and insufficient presentation in conventional ICD approaches. • Distinct regulation of different phagocytic cell types to block clearance while preserving antigen presentation • This study precisely regulates different phagocytic cell types by selectively blocking PS-dependent immunosilent efferocytosis in macrophages while preserving dendritic cell-mediated uptake through CRT pathways, ensuring efficient antigen presentation and subsequent immune activation. • Enhancement of macrophage antigen-presenting function to bridge ICD to adaptive immunity • Beyond conventional ICD strategies, this platform enhances the antigen-presenting capacity of macrophages, enabling effective antigen delivery to dendritic cells and T cells, bridging innate sensing with adaptive immune activation, and addressing the overlooked role of macrophages in ICD-based immunity. • Integration with immune checkpoint blockade to overcome immune inertia in cold tumors • By prolonging DAMPs exposure and remodeling the tumor microenvironment, P/A@MnO₂-M enhances responsiveness to αPD-L1 therapy, effectively overcoming immune inertia in cold tumors and demonstrating strong potential for synergistic immunotherapy. Immunogenic cell death (ICD) holds great promise for eliciting antitumor immunity but remains challenged by rapid signal clearance, insufficient antigen presentation, and dominant immunosuppression within the tumor microenvironment. Here, we report a sequential immune activation strategy through precise killing and phagocytosis regulation based on a porous MnO 2 -based nanoplatform (P/A@MnO 2 -M) integrating tumor-specific ICD induction with efferocytosis blockade for addressing transient ICD signals and immune tolerance. This nanotherapeutics prolongs danger signal exposure, prolonged immunogenic signaling, and strengthens immune activation upon a tumor membraned encapsulated carrier with co-delivery of PPE, a histone H1-targeting protease, and Annexin A5 (ANXA5), a PS-binding protein. Notably, it reprograms macrophages toward enhanced antigen presentation, facilitates dendritic cell activation and CD8 + T cell infiltration, completing the full ICD process from induction to adaptive immunity. In-vivo studies also confirm the synergistic anti-tumor effects of comprehensive tumor microenvironment remodeling and enhanced αPD-L1 efficacy, which offers a promising avenue for cancer immunotherapy. A tumor membrane-coated nanoplatform (P/A@MnO 2 -M) enables co-delivery of two functional proteins to induce ICD and suppress efferocytosis. This strategy ensures precise tumor killing, prolongs danger signal exposure, avoids immune cell damage, and preserves antigen-presenting processes. By supporting sustained DAMPs release and CD8 + T cell activation, it achieves full-course immune activation to remodel the immunosuppressive microenvironment in cold tumors. Download: Download high-res image (196KB) Download: Download full-size image