Intratumoural vaccination via checkpoint degradation-coupled antigen presentation
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons tumoraux et d'échantillons sanguins issus de patients atteints d'un cancer, cette étude met en évidence l'intérêt, pour restaurer l'immunité antitumorale, d'un vaccin intratumoral utilisant un anticorps anti-PD-L1 conjugué à des antigènes immunogènes
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 challenging1–3. 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.
Nature , article en libre accès, 2026