A versatile nanoplatform for enhancing the therapeutic efficacy against low-immunogenic TNBC by inducing immunogenic cell death and MHC-I upregulation

Triple-negative breast cancer (TNBC), characterized by low immunogenicity, is a challenging issue in clinical treatment due to its poor response to various therapies. The transformation of TNBC from a “cold tumor” with low immunogenicity into a “hot tumor” that elicits stronger immune responses is a key research focus. Photodynamic therapy (PDT) has emerged as a promising solution for TNBC treatment because it can effectively induce immunogenic cell death (ICD), which prompts the release of damage-associated molecular patterns (DAMPs) and activates immune responses. The role of MHC-I molecules in antigen presentation is crucial, but TNBC cells often evade immune surveillance by downregulating or losing MHC-I expression. Recent studies have shown that inhibiting the activity of complex II (CII) in the mitochondrial electron transport chain of tumor cells can promote MHC-I expression. Based on this finding, the combination of the PDT photosensitizer PCN-224 with the CII inhibitor 3-nitropropionic acid (3NPA) to form PCN@3NPA has been innovatively developed. Furthermore, modification with hyaluronic acid (HA) enables targeted delivery to TNBC cells that overexpress CD44. PDT induces ICD in tumor cells, releasing large amounts of DAMPs, while the sustained release of 3NPA effectively inhibits CII activity, significantly enhances MHC-I expression, thereby boosting tumor cell immunogenicity. This process significantly improves the recognition and killing of tumor cells by CD8 + T cells, markedly strengthening the body's anti-tumor immune response. This approach offers a novel and promising strategy for efficiently treating not only low-immunogenic TNBC but also other similar tumors, bringing new hope for future clinical treatments.