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Abstract Background: Esophageal cancer remains a lethal malignancy accounting for 604, 000 new cases and 544, 000 cancer-related modalities worldwide. To date, the clinical outcomes for patient with esophageal cancer are severely limited by the lack of effective treatment modalities. Moreover, the intrinsic and acquired resistances to chemotherapy and radiotherapy, stemming from DNA damage responses, inevitably exacerbates the disease progression. Pyroptosis is a proinflammatory programmed cell death (PCD) that is causally linked to anti-tumor immune responses, but the development of pyroptosis-based therapy has been limited by the lack of effective inducers to mediate pyroptotic cell death in a tumor-specific and controllable manner. Herein, we establishes that near-infrared light-triggered tumor pyroptosis (NIR-pyroptosis) is a novel non-apoptotic anticancer modality, providing a promising opportunity to overcome apoptosis resistance in current esophageal cancer therapies. Method: In this study, a novel esophageal cancer-targeted, NIR-pyroptosis antibody-drug conjugates (ADC) was established by covalently conjugating IRDye700, a photosensitizer, with ICAM1 antibody using thiol-maleimide click chemistry. This antibody-photosensitizer conjugate (ICAM1-IRDye700) functions as a potent NIR-pyroptosis inducer in multiple preclinical models of esophageal squamous cell carcinoma (ESCC). The in vitro potency of ICAM1-IRDye700 was determined by flow cytometry, immunofluorescent co-localization, and high-content imaging. Transmission electron microscopy (TEM) further characterized pyroptosis-related morphological changes in ICAM1-IRDye700-treated ESCC cells. To elucidate its underlying mechanism, transcriptomic and immune-blot analyses were performed to identify the molecular signaling cascades of NIR-pyroptosis ignited by ICAM1-IRDye700. Results: Under minimal doses (2ug/ml) of near-infrared light stimulation, ICAM1-IRDye700 rapidly triggered pyroptosis in ESCC cells, achieving approximately 95% cell death within 2 hours. Importantly, the potency of NIR-pyroptosis predominantly depends on the spatio. At different stages of drug accumulation on the cell membrane, in endosomes, and lysosomes, the time of pyroptosis induction varied. Transmission electron microscopy further observed pyroptosis-related morphological changes, and immunoblot analysis and sequencing results also provided supporting evidence, demonstrating the activation of the subcellular depositing locations of ICAM1-IRDye700 upon NIR irradiation. Further biomechanistic studies reveal that ICAM1-IRDye700 potently activates NLRP1-CASP1-GSDMD signaling axis, leading to a boosted antitumor immunity in vivo. This antitumor immunity activation was independent from reactive oxygen species (ROS). Furthermore, NIR-pyroptosis works in synergy with PD-1 immunotherapy by improving adaptive antitumor immunity in immunocompetent tumor models. Conclusion: Collectively, we established ICAM1-IRDye700 as a concept-of-proof ADC for NIR-pyroptosis therapy. Mechanistically, we explored the biomechanism of how ICAM1-IRDye700 igniting NIR-pyroptosis in ESCC tumors. This novel ADC boosts innate and adaptive immunity, resulting in potent and sustained tumor attenuations in combination with PD-1 checkpoint immunotherapy. Citation Format: Xue-Fei Tian, Fan Chen, Xi-Ru Xue, Yang Yang, Peng Guo. Near-infrared light-triggered tumor pyroptosis potentiates PD-1 immunotherapy in esophageal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB083.
Tian et al. (Fri,) studied this question.