Abstract Background: Targeted Hyperthermia Therapy (THT) delivers controlled intratumoral heating using gold nanorods that convert near-infrared (NIR) light into localized thermal energy. This minimally invasive approach induces immunogenic cell death (ICD) and reshapes the tumor microenvironment (TME). While preclinical studies have demonstrated that THT transiently inflames “cold” tumors, the mechanisms governing subsequent resistance and optimal combination strategies remain undefined. We present an early clinical evaluation of THT in humans, integrated with mechanistic B16F10 melanoma studies that define the immunogenic effects of controlled hyperthermia. Methods: In the first-in-human, open-label, early feasibility study (NCT06894407), ten patients with stage 3C/3D/4M1 cutaneous metastatic melanoma progressing on checkpoint inhibitors immunotherapy 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 a target intratumoral temperature of 42-48°C maintained for 5 minutes. Safety, feasibility, and early biological responses were assessed through adverse-event monitoring, photo documentation, and day-15 and 29 tumor biopsies. Results - Clinical: THT was well tolerated, with 31 adverse events reported across 10 patients. Most were mild (74%), with six moderate and two severe events; only two events were treatment-related and required intervention. No treatment-related serious adverse events occurred. By day 15, 8 of 10 patients exhibited clinical tumor regression in representative lesions. Complete histologic clearance was observed in 6 patients, and partial regression in 2, while 2 patients demonstrated no response. Results - Mechanistic Preclinical Studies: In B16F10 melanoma, controlled thermal dosing (42-48°C) induced a 24-48 h ICD response characterized by calreticulin and HSP70 exposure, chemokine and complement activation, and early TCR-clonal remodeling. Transcriptomic profiling showed a rapid transition from NF-κB- and TLR-driven innate activation to a Th2/M2-polarized repair program involving extracellular matrix remodeling and angiogenic stabilization. Higher thermal dose amplified immunosuppressive and regenerative pathways and reduced antigen presentation. CSF1R inhibition suppressed M2 macrophage accumulation, prevented tumor regrowth, and sustained antitumor inflammation, identifying immunosuppressive macrophages as a key barrier to durable responses after THT. Conclusions: THT demonstrates safety, feasibility, and rapid antitumor activity in patients with immunotherapy-refractory metastatic melanoma. Mechanistic analyses show that ICD transitions into a macrophage-dominated repair phase that limits durability. Defined thermal-dose parameters for immunogenic hyperthermia provide a rationale for combining THT with macrophage-modulating or checkpoint-based immunotherapies. Citation Format: Barry Kennedy, Carman Giacomantonio, Kate Clark, Julie Jordan, Cheryl Dean, Nick Cheverie, Kelly Corscadden, Caitlin Gormley, Geetha Subramanian, Erin Noftall, Alexander Roth. Targeted hyperthermia induces immunogenic tumor remodeling and demonstrates early clinical response in immunotherapy-refractory metastatic melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT066.
Kennedy et al. (Fri,) studied this question.