Biomimetic dual-driven STING nanoagonist orchestrates neoadjuvant mild photo-immunotherapy for fibrosarcoma

Fibrosarcoma is an infiltrative malignant soft tissue sarcoma primarily managed with extensive surgical resection. However, securing adequate margins often compromises organ function, while postoperative recurrence and distant metastasis remain formidable clinical challenges, underscoring the urgent need for effective neoadjuvant therapeutic strategies. Neoadjuvant mild photo-immunotherapy represents a promising strategy for coupling preoperative tumor shrinkage with systemic immune priming. Notably, integrated analyses revealed relatively high expression of stimulator of interferon genes (STING) in fibrosarcoma, highlighting STING as a rational target for immunomodulation. Herein, we developed a biomimetic dual-driven STING nanoagonist for neoadjuvant mild photo-immunotherapy against fibrosarcoma. This nanoagonist comprises poly(lactic-co-glycolic acid) (PLGA) nanoparticles co-encapsulating the STING agonist 2',3'-cyclic GMP-AMP (cGAMP) and the photosensitizer indocyanine green (ICG) (cGAMP/ICG@PLGA, GIP), which are further camouflaged with calreticulin (CRT)-enriched fibrosarcoma cell membranes (CRTM) to form GIP@CRTM. The biomimetic CRTM cloak retains tumor cell membrane antigens and CRT "eat-me" signals, promoting homotypic tumor accumulation and uptake by dendritic cells (DCs), thereby facilitating cGAMP delivery and dual-driven STING activation in both tumor cells and DCs. Upon near-infrared irradiation, ICG-mediated mild phototherapy induces moderate photothermal heating and reactive oxygen species (ROS) generation, triggering immunogenic cell death and further amplifying tumor-intrinsic STING signaling through ROS-induced DNA damage. This synergistic therapeutic effect enabled effective preoperative tumor shrinkage while eliciting systemic antitumor immunity to suppress postoperative contralateral rechallenge tumor outgrowth and limit distant tumor progression. Thus, this study establishes a STING-amplified mild photo-immunotherapeutic strategy, providing a potential neoadjuvant treatment option for fibrosarcoma.