Biomimetic PD-1-functionalized nanomedicine activates sting for durable antitumor immunity in HCC

HCC is characterized by low tumor antigenicity, inefficient antigen presentation, and insufficient or dysfunctional tumor-specific cytotoxic T cells. These features contribute to the limited response to immune checkpoint blockade. The STING pathway provides an important link between innate immune sensing and adaptive antitumor immunity. Its activation induces type I interferon signaling, promotes dendritic cell maturation, and enhances antigen cross-presentation.

The researchers first examined the clinical relevance of STING signaling instead of selecting the therapeutic target only from experimental models. Analysis of the TCGA-LIHC cohort showed that higher STING pathway activity was associated with improved overall and recurrence-free survival. In both the TCGA cohort and the institutional HCC cohort, STING signaling was positively correlated with antigen processing and presentation. Immune-hot tumors also showed stronger STING signaling than immune-cold tumors. In a clinical cohort treated with PD-1 blockade, responders exhibited higher enrichment of STING signaling and antigen presentation programs. These findings provided a data-driven basis for targeting STING in HCC.

Based on this rationale, the team designed a carrier-free coordination nanomedicine, MCI-NP. The small-molecule STING agonist MSA-2 and the photothermal agent ICG were co-assembled through Cu2+-mediated coordination. Under 808 nm near-infrared irradiation, ICG generates heat and induces immunogenic cell death. This process releases tumor antigens and damage-associated molecular patterns, while MSA-2 activates STING signaling and amplifies innate immune responses. The nanoparticle structure also improved the photostability of ICG. MCI-NP achieved a photothermal conversion efficiency of 52.3% and maintained stable photothermal performance during repeated irradiation.

At the cellular level, MCI-NP-mediated photothermal therapy effectively killed Hepa1-6 tumor cells and induced characteristic immunogenic cell death signals, including calreticulin exposure, HMGB-1 release, and extracellular ATP release. These signals promoted dendritic cell maturation. MCI-NP also increased the phosphorylation of STING, TBK1, and IRF3 and enhanced IFN-β secretion, confirming activation of the STING signaling cascade. In this way, photothermal tumor damage and STING-driven innate immune activation worked together to enhance antitumor immune responses.

However, the researchers also observed a potential mechanism of adaptive immune resistance. Strong immune activation was accompanied by increased IFN-γ and subsequent upregulation of PD-L1 in recurrent tumors. This could weaken the durability of the antitumor response through the PD-1/PD-L1 pathway. To address this problem, MCI-NP was coated with membranes derived from genetically engineered PD-1-overexpressing cells, producing MCI-NP@mPD-1. The membrane-displayed PD-1 served two functions: it enhanced tumor targeting through PD-1/PD-L1 recognition and acted as a decoy receptor to locally interfere with the PD-1/PD-L1 immune checkpoint.

The PD-1 membrane camouflage markedly improved tumor accumulation after intravenous administration. Tumor-associated fluorescence of MCI-NP@mPD-1 was approximately fivefold higher than that of uncoated MCI-NP, with maximum accumulation observed at 24 h. The resulting photothermal immunotherapy produced strong tumor growth inhibition and prolonged survival. It also increased pro-inflammatory and antitumor immune signals while reducing immunosuppressive factors, supporting a shift from an immune-cold toward a more immune-active tumor microenvironment.

Importantly, the therapeutic effect extended beyond control of the primary tumor. The integrated treatment promoted systemic antitumor immune memory and substantially limited postoperative pulmonary metastasis. These results show that the platform does more than combine photothermal ablation with a STING agonist. It also addresses treatment-induced adaptive immune resistance through biomimetic PD-1/PD-L1 blockade, allowing local tumor treatment to generate a more durable systemic immune response.

This work establishes a clinically guided strategy for immune-cold HCC. It begins with clinical cohort evidence for STING signaling and translates that finding into a biomimetic nanomedicine that integrates photothermal-induced immunogenic cell death, STING activation, and localized immune checkpoint blockade. The resulting immune reprogramming and systemic immune memory provide a promising framework for improving the durability of HCC immunotherapy.

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

Journal Name: Nano-Micro Letters

DOI: https://doi.org/10.1007/s40820-026-02320-7

URL: https://scholarcast.cast.org.cn/top-news/2104551419010846720