Immune-Activating Cationic Lipo-Polypeptides for Oncolytic Immunotherapy in Triple Negative Breast Cancer
Triple negative breast cancer (TNBC) exhibits an exceptionally low responsiveness to immunotherapy due to its immunologically cold tumor microenvironment (TME), characterized by poor T-cell infiltration and abundant immunosuppressive cells. We synthesized a series of immune-activating lipo-polylysines (IAP-1 to IAP-9) with varying carbon chain and polylysine segment lengths, and evaluated their oncolytic and immunogenic cell death (ICD)-inducing activities. Both activities are structure-dependent. IAP-4 demonstrated the most potent oncolytic and ICD-inducing capabilities in 4T1 tumor cells, inducing necrosis via membrane lysis and mitochondrial damage, and triggering ICD as evidenced by calreticulin exposure, ATP secretion, and HMGB1 release. In vivo, IAP-4 remodeled the TME by enhancing cytotoxic T lymphocyte infiltration and reducing immunosuppressive components, converting cold tumors to hot. This led to inhibition of primary tumors, suppression of recurrence and metastasis, and establishment of antitumor immune memory. This drug-free strategy offers a promising approach for TNBC immunotherapy, with structure-activity relationships providing a framework for designing next-generation oncolytic agents.