T-cell hitchhiking nanodrug activates the cGAS-STING signaling pathway for enhanced cancer immunotherapy.

Abstract

Despite the clinical success of immune checkpoint blockade (ICB) in cancer therapy, its efficacy against "cold" tumors like triple-negative breast cancer (TNBC) remains limited due to low immunogenicity and an immunosuppressive microenvironment. Emerging evidence suggests activating the cGAS-STING pathway to enhance antigen presentation is an effective strategy to turn TNBC from "cold" to "hot". Herein, we developed a nanodrug MnO@PPC-aPD-1 that incorporates MnO nanoparticles and anti-PD-1 antibodies (aPD-1) to overcome these limitations. The MnO@PPC-aPD-1 exploits T cell homing through surface-conjugated aPD-1 for tumor-specific delivery. Upon reaching the acidic tumor microenvironment (TME), the system releases aPD-1 to block immune checkpoints while simultaneously activating the cGAS-STING pathway in both antigen presenting cells and tumor cells via MnO@PPC. This dual action not only enhances antigen presentation but also suppresses immunosuppressive signals including ENPP1, NLRC3, and non-canonical NF-κB, effectively converting "cold" tumors to "hot". The treatment establishes a positive feedback loop by recruiting and activating tumor-infiltrating T cells, while generating memory T cells to prevent metastasis and recurrence. Our findings provide mechanistic insights into tumor immunogenicity modulation and demonstrate a promising approach for enhancing ICB efficacy in poorly immunogenic cancers. STATEMENT OF SIGNIFICANCE: Inadequate immune activation and lack of specific targets hinder effective immunotherapy for triple-negative breast cancer (TNBC). Here, we developed a tumor-agnostic delivery system-a T cell-hitchhiking nanodrug (MnO@PPC-aPD-1). This system leverages T cell homing via surface-conjugated aPD-1 for tumor-specific delivery, responding to the mildly acidic tumor microenvironment to release aPD-1 for checkpoint blockade. Concurrently, MnO@PPC activates the cGAS-STING pathway in both antigen-presenting cells and tumor cells. This dual mechanism not only enhances antigen presentation but also suppresses immunosuppressive signals (including ENPP1, NLRC3, and non-canonical NF-κB), effectively converting "cold" tumors to "hot." The therapy establishes a self-reinforcing cycle by recruiting and activating tumor-infiltrating T cells while generating memory T cells to prevent metastasis and recurrence.