The role of OX40 in cancer immunotherapy: A comprehensive review from mechanisms to clinical applications.

OX40 (CD134), a key member of the tumor necrosis factor receptor superfamily, provides an indispensable co-stimulatory signal for T cell activation. This review systematically elucidates the molecular biology of the OX40/OX40L significant synergistic efficacy signaling axis and its multifaceted roles and significant potential in cancer immunotherapy. This pathway, through the activation of NF-κB, PI3K/Akt, and other signaling cascades, promotes the proliferation, survival, and function of effector T cells while effectively inhibiting regulatory T cell (Treg) function and remodeling the immunosuppressive tumor microenvironment (TME), thereby exerting potent anti-tumor effects. However, the prognostic value of OX40 expression is tumor-type specific, and although monotherapy clinical trials have confirmed its favorable safety profile, the objective response rates remain limited. Importantly, the interpretation of OX40 expression must consider its cellular compartment-whether it is expressed on effector T cells or Tregs-as these subsets exert opposing immune functions. Furthermore, whether OX40 is a causal driver of anti-tumor immunity or merely a surrogate marker of an inflamed TME remains an open question that impacts its therapeutic targeting. This has driven a comprehensive shift in research focus towards combination therapies. Currently, various combination strategies (e.g., with immune checkpoint inhibitors, radiotherapy, cell therapies, and metabolic modulators) and the development of next-generation agonists (such as hexavalent antibodies and bispecific molecules) are demonstrating significant synergistic efficacy in preclinical studies and early-phase trials. Despite challenges including the lack of precise biomarkers and the difficulty in reversing the immunosuppressive TME, optimized combination regimens, innovative drug design, and the utilization of the neoadjuvant treatment window hold promise for breakthroughs in precision immunotherapy targeting OX40 within the future landscape of comprehensive cancer treatment.