Photothermal immunomodulatory nanoagents synchronize immunogenic cell death and TAM reprogramming for colorectal cancer immunotherapy.

The immunosuppressive tumor microenvironment (TME) continues a critical obstacle to effective colorectal cancer immunotherapy. A photothermal immunomodulatory nanoagent was developed to sequentially ignite immunogenic cell death (ICD) and reprogram tumor-associated macrophage (TAM) through stimuli-responsive cascade actions, thereby enhancing antitumor effect. The hybrid nanoagent (MIB@HA) containing hollow manganese dioxide (H-MnO2), indocyanine green (ICG), and thermosensitive nitric oxide (NO) donor (BNN6) is synthesized and subsequently camouflaged with hyaluronic acid (HA). Through HA mediated recognition, MIB@HA achieves efficient tumor enrichment and prolonged tumor retention. Upon laser irradiation, the ICG-mediated photothermal effect simultaneously amplifies MnO2-enabled chemodynamic therapy (CDT) to induce ICD and triggers on-demand NO release. The released NO promotes macrophage polarization toward an antitumor M1-like phenotype and synergizes with T-cell infiltration, thereby improving the conversion of local therapy into productive antitumor immunity. In the mouse model of colorectal cancer, this approach promotes the infiltration of antitumor macrophages and effector T cells into tumor sites for effective colorectal cancer immunotherapy. By synchronizing ICD induction with NO-driven TAM reprogramming under a single external trigger, this work provides a programmable strategy to enhance antitumor immunity.