First-in-human evaluation and preclinical mechanistic studies of targeted hyperthermia therapy.

2595 Background: Photothermal conversion of near-infrared (NIR) light using specifically tuned, directly delivered gold nanorods produces controllable hyperthermia in tumor microenvironments. Precisely controlled, targeted hyperthermia therapy (THT) induces immunogenic cell death (ICD) and remodels the tumor microenvironment, promoting immune activation in otherwise poorly inflamed tumors. Here, we report an early clinical evaluation of THT integrated with mechanistic preclinical analyses. Preclinical studies: In B16F10 melanoma and CT26 colorectal models, controlled thermal dosing induced a 24–48 h ICD response marked by calreticulin and HSP70 exposure, chemokine and complement activation, and early T-cell receptor remodeling. Transcriptomic analyses revealed a dose-dependent transition from innate immune activation to a coordinated tissue repair program involving extracellular matrix remodeling. Lower thermal doses in the hyperthermic window decreased regulatory pathways and induced antigen presentation. Modulation of myeloid signaling limited macrophage accumulation, prevented tumor regrowth, and sustained antitumor inflammation. Methods: In a first-in-human, open-label, early feasibility study (NCT06894407), ten patients with stage IIIc/IIId/IV M1 cutaneous metastatic melanoma progressing on checkpoint inhibitor therapy received intratumoral gold nanorods (Sona Nanotech Inc.) followed by NIR-mediated heating on days 1 and 8. Up to four lesions per patient were treated, with intratumoral temperatures maintained at 42–48 °C for 5 minutes. Safety, feasibility, and early biological activity were assessed through adverse-event monitoring, clinical photography, and tumor biopsies obtained on days 15 and 29. Results: Clinical: THT was well tolerated, with no treatment-related serious adverse events observed. By day 15, 8 of 10 patients demonstrated regression in treated lesions. Histologic assessment showed complete tumor clearance in 6 patients, partial regression in 2 patients, and no response in 2 patients. Conclusions: THT-induced ICD progresses through temporally regulated immune states, including a reparative myeloid-associated phase that limits durability. Defined thermal-dose parameters provide a framework for rational integration of THT with macrophage-modulating and checkpoint-based immunotherapies. THT is safe, feasible, and biologically active in immunotherapy-refractory metastatic melanoma. Further clinical studies are needed to evaluate the efficacy of THT in immune-refractory cancers. Clinical trial information: NCT06894407 .