Targeted modulation of cancer-associated fibroblast subtype remodels the tumor extracellular matrix to enhance photoimmunotherapy in hepatocellular carcinoma

Photothermal therapy (PTT) shows considerable potential for cancer treatment owing to its ability to activate potent antitumor immune responses. However, the dense extracellular matrix (ECM) produced by fibroblast activation protein (FAP) + cancer-associated fibroblasts (CAFs) restricts the efficacy of photoimmunotherapy by forming an immunosuppression barrier in hepatocellular carcinoma (HCC). In this study, we developed a nanoplatform (FP@DCNP) to deliver celastrol (CEL), an antifibrotic modulator, enabling the modulation of CAF-mediated ECM remodeling and enhancement of photoimmunotherapy. This platform incorporates a newly synthesized organic semiconducting photosensitizer, DPPFB, which exhibits secondary near-infrared window (NIR-II) photonic properties suitable for NIR-II-imaging-guided cancer therapy. FAP-targeting peptide-modified nanoparticles co-encapsulating CEL and DPPFB selectively bind to CAFs within the tumor stroma, thereby promoting intratumoral penetration and cellular uptake. Mechanistically, CEL ablates FAP⁺-CAF-mediated ECM desmoplasia by modulating the Hippo pathway, thereby enhancing photosensitizer penetration and cytotoxic lymphocyte infiltration. Subsequently, mild PTT mediated by DPPFB induces immunogenic cell death to promote cytotoxic lymphocyte recruitment and systemic antitumor immunity. Concurrently, the integrated delivery of CEL and DPPFB activates adenosine 5′-monophosphate-activated protein kinase-dependent PD-L1 degradation to synergistically reverse tumor immune evasion. In the HCC mouse model, this therapeutic strategy amplifies the efficacy of photoimmunotherapy, effectively ablating primary tumors and inhibiting distant metastases. Importantly, FP@DCNP-mediated unilateral phototherapy triggers a robust immune-mediated abscopal effect, resulting in the effective inhibition of distant tumor growth. Overall, this study establishes CAF-targeted ECM remodeling as an effective strategy for enhancing photoimmunotherapy, revealing a synergistic interplay between stromal modulation and checkpoint inhibition for the treatment of immunologically “cold” tumors. Scheme 1. Schematic representation of the FAP⁺-CAF-targeted nanoparticles (FP@DCNP), which remodel the ECM to enhance photoimmunotherapy in HCC. (A) Synthesis and structural composition of FP@DCNP and its specific targeting of FAP⁺ CAFs. (B) Schematic representation showing FP@DCNP targeting FAP⁺ CAFs to remodel the ECM, thereby enhancing PTT-induced immune activation and its underlying mechanism.