Camptothecin Nanowires Induce the cGAS-STING Pathway to Remold Tumor-Associated Macrophages for Antitumor Immunity

Background/Objectives: This study aimed to develop a novel tumor-associated macrophage (TAM)-targeting nanoplatform to improve the solubility and bioavailability of camptothecin (CPT) and achieve active targeted drug delivery for enhanced anti-tumor immunotherapy. Methods: We constructed a sialic acid-disulfide bond-camptothecin (SA-SS-CPT) nanowire system. Sialic acid was used as a targeting ligand to specifically recognize the overexpressed Siglec-E receptor on TAMs. Upon cellular internalization, the disulfide bond was designed to respond to intracellular glutathione (GSH), enabling controlled drug release. Results: The SA-SS-CPT nanowires significantly improved CPT solubility and enabled targeted delivery to TAMs. Following GSH-responsive cleavage and CPT release, the nanowires induced DNA damage in TAMs, activating the cGAS-STING signaling pathway. This promoted TAM polarization toward the M1 phenotype, enhanced pro-inflammatory and anti-tumor immune responses, and inhibited tumor immune escape. Furthermore, SA-SS-CPT synergistically improved the efficacy of PD-L1 blockade immunotherapy, remodeling the tumor immune microenvironment. Conclusions: The SA-SS-CPT nanoplatform effectively targets TAMs, repolarizes them to an anti-tumor M1 phenotype, and activates the cGAS-STING pathway. It shows strong potential for overcoming tumor immune escape and synergizing with PD-L1 checkpoint blockade to achieve significant tumor clearance.