OX40 and its ligand OX40L are critical components of the immune system, playing a key role in T-cell activation and immune regulation. These molecules belong to the tumor necrosis factor receptor superfamily and are involved in enhancing immune responses against cancer. OX40 is expressed on activated T cells, while OX40L is primarily found on antigen-presenting cells. The interaction between OX40 and OX40L promotes T-cell survival, proliferation, and cytotoxicity, and helps to suppress regulatory T cells (Tregs), which can inhibit immune responses. OX40 agonists, which stimulate the OX40 pathway, are being investigated as potential cancer therapies, either as monotherapy or in combination with other immunotherapies. Preclinical studies have shown that OX40 agonists can enhance anti-tumor immunity by increasing T-cell activity and reducing the suppressive effects of Tregs. However, clinical trials have shown that only a minority of patients respond to OX40 agonists, suggesting that the effectiveness of these therapies may depend on the expression levels of OX40 and OX40L in the tumor microenvironment. Transcriptomic analysis has revealed that OX40 and OX40L expression varies between and within different tumor types, with a specific pattern of high OX40 and low OX40L expression being associated with a potentially favorable response to OX40 agonists. This pattern is observed in about 17% of cancer patients, most commonly in lung and breast cancers. Early-phase clinical trials have demonstrated that OX40 agonists can induce immune responses in advanced solid tumors, although the response rate remains low. The effectiveness of OX40 agonists may be influenced by factors such as the expression of other immune checkpoints, the tumor microenvironment, and the presence of other immune regulatory molecules. Current research is focused on understanding the role of OX40 and OX40L in cancer immunotherapy and exploring their potential as targets for precision oncology. Future studies may aim to identify biomarkers that can predict which patients are most likely to benefit from OX40 agonist therapy, thereby improving the efficacy of these treatments.OX40 and its ligand OX40L are critical components of the immune system, playing a key role in T-cell activation and immune regulation. These molecules belong to the tumor necrosis factor receptor superfamily and are involved in enhancing immune responses against cancer. OX40 is expressed on activated T cells, while OX40L is primarily found on antigen-presenting cells. The interaction between OX40 and OX40L promotes T-cell survival, proliferation, and cytotoxicity, and helps to suppress regulatory T cells (Tregs), which can inhibit immune responses. OX40 agonists, which stimulate the OX40 pathway, are being investigated as potential cancer therapies, either as monotherapy or in combination with other immunotherapies. Preclinical studies have shown that OX40 agonists can enhance anti-tumor immunity by increasing T-cell activity and reducing the suppressive effects of Tregs. However, clinical trials have shown that only a minority of patients respond to OX40 agonists, suggesting that the effectiveness of these therapies may depend on the expression levels of OX40 and OX40L in the tumor microenvironment. Transcriptomic analysis has revealed that OX40 and OX40L expression varies between and within different tumor types, with a specific pattern of high OX40 and low OX40L expression being associated with a potentially favorable response to OX40 agonists. This pattern is observed in about 17% of cancer patients, most commonly in lung and breast cancers. Early-phase clinical trials have demonstrated that OX40 agonists can induce immune responses in advanced solid tumors, although the response rate remains low. The effectiveness of OX40 agonists may be influenced by factors such as the expression of other immune checkpoints, the tumor microenvironment, and the presence of other immune regulatory molecules. Current research is focused on understanding the role of OX40 and OX40L in cancer immunotherapy and exploring their potential as targets for precision oncology. Future studies may aim to identify biomarkers that can predict which patients are most likely to benefit from OX40 agonist therapy, thereby improving the efficacy of these treatments.