pH-responsive in situ antigen capture and cytosolic delivery synergize to elicit robust systemic antitumor immunity

In situ cancer vaccines hold strong potential for addressing tumor heterogeneity by using the patient’s own tumor as a personalized antigen source. However, their efficacy remains limited by insufficient antigen capture and inefficient cytosolic delivery. Here, we report an in situ antigen capture and delivery platform, DOX/PDiT@Gel, in which the pH-responsive function is provided by the polymer PDiT, while the hydrogel serves as a local retention matrix. In this system, doxorubicin (DOX) and a cationic polymer, PEG-DIPAMA-TAT (PDiT), are co-encapsulated within an oxidized dextran/carboxymethyl chitosan hydrogel. DOX induces immunogenic cell death, releasing diverse tumor antigens, while PDiT captures these antigens in situ via electrostatic interactions and promotes endo/lysosomal escape under acidic conditions. The hydrogel allows localized delivery of the therapeutic components at the postoperative tumor site. In vitro studies showed that PDiT markedly promoted antigen internalization, cross-presentation, and dendritic cell maturation. In murine models of postoperative recurrence and bilateral breast tumors, local treatment with DOX/PDiT@Gel inhibited the growth of both recurrent and distant tumors, together with stronger dendritic cell activation and enhanced memory T cell responses. Overall, this platform effectively amplifies antitumor immunity and offers a versatile strategy for personalized cancer immunotherapy.