Self-Assembled Manganese-Based Nanoplatforms Synergizing Immunogenic Cell Death and STING Activation for Triple-Negative Breast Cancer

: Tumor immunotherapy has emerged as a promising approach to eliminate cancer by activating host immunity but shows limited efficacy in triple-negative breast cancer (TNBC) due to its low immunogenicity and an immunosuppressive tumor microenvironment (TME). In this study, we developed a manganese-based nanoparticle, termed HLM315, via one-step self-assembly of alendronate-modified hyaluronic acid (HA-AL), the amphiphilic cationic peptide LTX-315, and Mn 2+ under weakly alkaline conditions. HLM315 actively targeted tumors and responded to the TME, releasing LTX-315 and generating Mn 2+ . LTX-315 induced immunogenic cell death (ICD) through tumor membrane disruption and release of tumor antigens and damage-associated molecular patterns (DAMPs), thereby providing an initial signal for immune activation. Meanwhile, Mn 2+ generated reactive oxygen species (ROS) and amplified the cGAS-STING signaling. Together, these mechanisms synergistically promoted type I interferon production, dendritic cells (DCs) maturation, T-cell recruitment and activation, and elicited an enhanced immunological memory. Ultimately, HLM315 systematically reshaped the TME and potently inhibited the tumor growth in TNBC orthotopic mouse model. Overall, HLM315 establishes a coordinated antitumor immune cascade and offers a promising strategy to enhance immunotherapy efficacy in TNBC.