肿瘤坏死因子受体家族的共刺激成员，如O×40(CD134)，提供了必要的生存和分化信号，增强T细胞的功能。具体来说，O×40(CD134)激动剂在各种临床前模型中刺激强大的抗肿瘤免疫力，但在晚期恶性肿瘤患者中的治疗影响迄今为止有限。在本综述中，我们讨论了包括临床前研究和最新临床试验在内的O×40激动剂联合免疫疗法的现状。我们还讨论了这些方法的优势和局限，并提供了对可能有助于提高组合O×40激动剂免疫疗法效果的替代方法的见解。O×40激动剂免疫疗法在单一疗法或与免疫检查点阻断（ICB）联合应用中尚未展示出显著的临床活性，这可能与多种因素有关，包括给药时机、药物效力以及选择用于组合疗法临床试验的药物。我们认为，对调控O×40表达和功能的生物学机制进行仔细考虑，可能有助于指导新的方法，特别是与新型药物联合应用，以提高该方法的治疗效果。

Costimulatory members of the tumor necrosis factor receptor family, such as O×40(CD134), provide essential survival and differentiation signals that enhance T cell function. Specifically, O×40(CD134) agonists stimulate potent anti-tumor immunity in a variety of preclinical models but their therapeutic impact in patients with advanced malignancies has been limited thus far.In this review, we discuss the current state of combination immunotherapy with O×40agonists including preclinical studies and recent clinical trials. We also discuss the strengths and limitations of these approaches and provide insight into alternatives that may help enhance the efficacy of combination O×40agonist immunotherapy.OX40 agonist immunotherapy has not yet demonstrated significant clinical activity as a monotherapy or in combination with immune checkpoint blockade (ICB), likely due to several factors including the timing of administration, drug potency, and selection of agents for combination therapy clinical trials. We believe that careful consideration of the biological mechanisms regulating O×40expression and function may help inform new approaches, particularly in combination with novel agents, capable of increasing the therapeutic efficacy of this approach.