The ITGB2/ICAM-1 axis: biological functions and therapeutic promise in cancer

Integrin ITGB2 (β2, CD18) and its ligand ICAM-1 are critical mediators of immune homeostasis, governing leukocyte homing to sites of inflammation. ITGB2 and ICAM-1 inhibitors were therefore evaluated in the clinic as therapeutics aimed at suppressing inflammation, but development was halted due to adverse immune events that stalled interest in these targets. Three converging advances are now reenergizing the field. First, the ITGB2/ICAM-1 axis is increasingly recognized as a prominent regulator of the tumor microenvironment (TME), extending far beyond its classic role in leukocyte trafficking. Second, cancer cell-intrinsic ITGB2, alone or in concert with ICAM-1, has emerged as a previously overlooked mechanism of tumor cell proliferation and metastasis. Third, advances in cell type-directed strategies, including cancer cell targeting approaches, now offer the potential to selectively engage ITGB2/ICAM-1, enabling local rather than systemic therapy to circumvent toxicity. Within neoplastic settings, the ITGB2/ICAM-1 axis thus exerts pleiotropic, lineage-dependent functions across immune, stromal, and malignant compartments, acting as a double-edged sword that can either fuel cancer progression or restrain antitumor immunity, depending on cellular context. Despite such pivotal roles, the biology of these molecules, including their tumor-intrinsic activity, remains underexplored in oncology, leaving substantial therapeutic potential untapped. In this review, we dissect ITGB2 and ICAM-1 functions, from classic leukocyte homing mechanisms to lesser studied non-adhesive and tumor cell-intrinsic roles across physiological and malignant contexts. Moving beyond historical clinical roadblocks, we propose precision, immune or tumor cell-directed strategies to selectively activate or inhibit ITGB2/ICAM-1 signaling. This work outlines an innovative framework for targeting the ITGB2/ICAM-1 axis to rewire the TME and synergize with adoptive cell and checkpoint immunotherapies.