IL-1α Blockade Sensitizes HNSCC to Photodynamic Therapy by Reversing Hypoxia and NF-κB Resistance

Photodynamic therapy (PDT) offers a minimally invasive option for superficial lesions, but its effectiveness is often hampered in hypoxic tumors like head and neck squamous cell carcinoma (HNSCC). Current strategies to overcome this hypoxia-induced resistance, often involving complex nanomaterials, face significant translational hurdles. There's a critical need to identify actionable molecular targets within the tumor's heterogeneous microenvironment to improve PDT outcomes. This study investigates such targets, focusing on pathways that confer resistance to PDT-induced oxidative stress.

Researchers employed spatial transcriptomic profiling on HNSCC specimens to map molecular gradients within hypoxic regions, identifying IL1A as a key upregulated transcript. Functional analyses were then conducted using various cellular models and patient-derived organoids (PDOs) to investigate the role of IL-1α in PDT resistance. The study specifically evaluated the impact of the selective IL-1R1 antagonist AF12198 on PDT efficacy, assessing its ability to disrupt the identified resistance axis. The primary endpoint was enhanced PDT efficacy, measured by reversing oxidative stress resistance.

Spatial transcriptomic profiling revealed IL1A as the most significantly upregulated transcript within hypoxic niches of HNSCC specimens, a finding that directly correlated with adverse clinical outcomes. Furthermore, PDT itself amplified IL-1α expression, establishing a self-reinforcing resistance loop. Functional studies confirmed that hypoxic tumor-derived IL-1α activates the NF-κB pathway, which in turn confers resistance against PDT-induced oxidative stress. Critically, the selective IL-1R1 antagonist AF12198 disrupted this IL-1α/IL-1R1/NF-κB resistance axis. > Pharmacological blockade with AF12198 significantly enhanced PDT efficacy across both cellular models and patient-derived organoids (PDOs), demonstrating a potent reversal of intrinsic PDT resistance. This suggests a direct, actionable link between IL-1α signaling and tumor cell survival under PDT.