Intratumoural vaccination via checkpoint degradation-coupled antigen presentation.

Abstract

Decreased cross-presentation by antigen-presenting cells induces the scarcity of tumour-reactive T cells within the tumour bed, rendering in situ T cell rejuvenation through immunogenicity reprogramming highly desirable yet challenging^1-3. Here we developed an intratumoural vaccination chimera (iVAC) to reprogram tumour cells into an antigen-presenting state (APC-like tumour cells) with restored anti-tumour immunity. The iVAC chimeras consist of a covalently engineered PD-L1 degrader conjugated to immunogenic antigens, which could relieve immune checkpoint inhibition while enforcing the cross-presentation of exogenous antigens. Functionally, the iVAC-induced antigen processing and presentation elicited potent tumour killing through reactivation of resident antigen-specific CD8⁺ T cells, which simultaneously remodelled the tumour microenvironment to promote durable tumour-specific immunity. Extending this strategy, we used iVAC with a cytomegalovirus (CMV)-derived antigen to activate CMV-specific T cells against breast cancer in vitro, in a humanized mouse model as well as in a patient-derived tumour model. This study establishes a foundation for chemically reprogramming cancer cells within tumour beds to endow APC-like functions, providing an avenue for stimulating anti-tumour immunity.