ICAM-1 promotes T cell glycolytic reprogramming and tumor infiltration to drive 18F-FDG PET flares following radiotherapy

Radiotherapy (RT) is one of the most widely used cancer treatment modalities, applied in over half of all patients with cancer. In clinical oncology, positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) is widely used to noninvasively monitor tumor glucose metabolism and evaluate therapeutic responses, including those to RT. However, transient increases in ¹⁸F-FDG uptake—referred to as post-RT “metabolic flares”—are frequently observed in responding tumors and have traditionally been attributed to localized inflammatory reactions. Whether these flares reflect underlying immune cell dynamics, particularly tumor-infiltrating T cells, has remained poorly understood.

In this study, through integrated analyses of patient samples and multiple mouse tumor models, RT was shown to robustly induce intracellular adhesion molecule-1 (ICAM-1) expression within tumors and to promote T cell infiltration. Genetic ablation of ICAM-1 markedly attenuated RT-induced ¹⁸F-FDG flares, an effect primarily attributable to reduced glucose uptake and tumor infiltration of T cells rather than myeloid cells. Mechanistically, RT-induced ICAM-1 engages lymphocyte function-associated antigen-1 (LFA-1) to facilitate T cell clustering and intratumoral accumulation, thereby activating the PI3K–AKT–mTOR signaling pathway and driving metabolic reprogramming characterized by enhanced glycolysis and tricarboxylic acid (TCA) cycle activity.

This study establishes ICAM-1 as a key regulator of T cell metabolic reprogramming and tumor infiltration following RT. These findings offer a mechanistic framework for more accurate interpretation of post-RT PET imaging, support the use of ICAM-1 as a biomarker to distinguish pseudoprogression from true tumor progression, and provide new avenues for monitoring antitumor immune dynamics and optimizing RT-based combination therapies.

Radiotherapy-induced ICAM-1 upregulation promotes T cell clustering through ICAM-1–LFA-1 interactions, activates PI3K–AKT–mTOR signaling, and thereby drives T cell glycolytic reprogramming and tumor infiltration, leading to ¹⁸F-FDG PET flares