Abstract

Photodynamic therapy (PDT) provides non-invasive precision for superficial lesions but achieves suboptimal responses in hypoxic tumors such as head and neck squamous cell carcinoma (HNSCC). Spatially heterogeneous resistance mechanisms pose a major translational constraint for extending PDT applicability. To overcome this limitation, actionable targets were mapped within tumor spatial heterogeneity, circumventing conventional nanomaterial-based hypoxia-reversal strategies with inherent design complexity and protracted translation timelines. Spatial transcriptomic profiling of HNSCC specimens revealed pronounced molecular gradients along hypoxic regions, pinpointing IL1A as the most significantly upregulated transcript in hypoxic niches, which directly correlates with adverse clinical outcomes. PDT further amplified IL-1α expression, establishing a self-reinforcing resistance loop. Functional analyses confirmed that hypoxic tumor-derived IL-1α activates the NF-κB pathway to confer resistance against PDT-induced oxidative stress. Critically, the selective IL-1R1 antagonist AF12198 disrupted this resistance axis, significantly enhancing PDT efficacy across cellular models and patient-derived organoids (PDOs). Pharmacological blockade of the IL-1α/IL-1R1/NF-κB axis represents a clinically actionable strategy against intrinsic PDT resistance. By leveraging spatial heterogeneity to identify IL-1α as a druggable target, this study provides robust preclinical support for repurposing clinical IL-1 inhibitors to enhance PDT efficacy.