Biomimetic PD-1-Functionalized Immunostimulatory Nanomedicine Enables STING Activation and Durable Antitumor Immunity in Hepatocellular Carcinoma

Abstract

Clinical cohort analyses identify stimulator of interferon genes (STING) signaling as a key determinant of immune responsiveness in hepatocellular carcinoma (HCC), providing a data-driven rationale for nanomedicine design. A carrier-free coordination nanomedicine co-assembles MSA-2 and indocyanine green to couple photothermal-induced immunogenic cell death with STING activation, while PD-1 membrane camouflage enables ~fivefold tumor accumulation and localized checkpoint blockade. This integrated strategy converts immune-cold HCC into an immune-active state, achieving durable tumor control and systemic immune memory against metastasis. Clinical cohort analyses identify stimulator of interferon genes (STING) signaling as a key determinant of immune responsiveness in hepatocellular carcinoma (HCC), providing a data-driven rationale for nanomedicine design. A carrier-free coordination nanomedicine co-assembles MSA-2 and indocyanine green to couple photothermal-induced immunogenic cell death with STING activation, while PD-1 membrane camouflage enables ~fivefold tumor accumulation and localized checkpoint blockade. This integrated strategy converts immune-cold HCC into an immune-active state, achieving durable tumor control and systemic immune memory against metastasis. Hepatocellular carcinoma (HCC) responds poorly to immune checkpoint blockade, largely because of an immunologically cold tumor microenvironment (TME) characterized by deficient antigen presentation and impaired cytotoxic T cell responses. Analysis of numerous HCC clinical cohorts, including our institutional datasets, reveals that stimulator of interferon genes (STING) pathway activity is positively correlated with patient survival, enhanced antigen presentation capacity, and an immune-activated TME. However, achieving effective and controllable STING activation in immune-cold HCC tumors remains challenging. Here, we develop a biomimetic nanomedicine that integrates photothermal therapy (PTT), STING pathway activation, and immune checkpoint blockade to treat refractory HCC. A coordination nanomedicine MCI-NP is engineered by co-encapsulating the STING agonist MSA-2 and indocyanine green (ICG) via Cu2+-mediated chelation, enabling stabilized PTT-induced immunogenic cell death together with robust STING-driven innate immune activation. Further cloaked with PD-1-overexpressing cell membranes, MCI-NP@mPD-1 achieves an approximately fivefold increase in tumor accumulation compared with uncoated MCI-NP and enables localized PD-1/PD-L1 axis blockade. Following a single treatment, MCI-NP@mPD-1-based photothermal immunotherapy effectively suppresses primary tumor growth and significantly prolongs survival by remodeling the TME toward an immune-active state, while inducing durable systemic immune memory that effectively limited postoperative lung metastasis. Without introducing additional nanocarriers or excipients, MCI-NP@mPD-1 offers a promising therapeutic paradigm for photothermal immunotherapy of immune-cold HCC.