Immune-activating cationic lipo-polypeptides for oncolytic immunotherapy in triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) exhibits an exceptionally low responsiveness to immunotherapy due to its “cold” tumor immune microenvironment. It is urgent to design a rational therapy to reverse “cold” tumors into “hot” ones to improve the therapeutic effects. In this study, we developed a series of immune-activating lipo-polylysine (IAPs), designated as IAP-1 to IAP-9, that display both oncolytic and immunogenic cell death (ICD)-inducing activities. It is confirmed that both oncolytic activity and ICD-inducing capacity of IAPs are structure-dependent. Among them, IAP-4 exhibits the most effective oncolytic and ICD-inducing capabilities in 4T1 tumor cells. Mechanistic investigations suggest that IAP-4 can induce cancer cell necrosis through a membrane-lytic mechanism and trigger potent ICD of tumor cells through membrane lysis and mitochondrial damage. In vivo antitumor activity determination results indicate that IAP-4 effectively converses cold tumors to hot by inducing ICD. This process not only inhibits primary tumors but also elicits specific antitumor immune memory, leading to a significant suppression of tumor recurrence and metastasis. Briefly, this work pioneers a promising drug-free strategy for oncolytic immunotherapy.