Although anti-PD-1/L1 and anti-CTLA-4 antibodies, the validated immune checkpoint blockades, can elicit durable long-lasting antitumor immunity and improve the clinical outcomes of melanoma treatment, there are still a fraction of patients who did not receive therapeutic benefits as expected. In addition to findings of blocking the co-inhibitory pathways, the preclinical and clinical evidence suggests that triggering the co-stimulatory pathways through agonists such as CD137, OX40, CD40, GITR and CD27 may be a rational next step for melanoma therapy. In this review, we discuss the progress of studies on these co-stimulatory molecules in terms of their promising therapeutic effects and underlying antitumor mechanisms, and provide a review of the possible combinations that orchestrate the interplay of co-stimulatory agonistic mAbs and other therapies for treating melanoma, including inhibitory immune checkpoint mAbs, adoptive T cell therapy, chemotherapy and radiotherapy. We also briefly present the limitations and challenges involved in these co-stimulatory agonistic mAb-based combination strategies for melanoma patients.

尽管抗PD-1 / L1和抗CTLA-4抗体（已验证的免疫检查点阻滞剂）可以引发持久的持久抗肿瘤免疫力并改善黑色素瘤治疗的临床结果，但仍有一部分患者未接受治疗预期的治疗效果。除了阻断共抑制途径的发现外，临床前和临床证据还表明，通过激动剂（例如CD137，OX40，CD40，GITR和CD27）触发共刺激途径可能是黑色素瘤治疗的合理下一步。在这篇综述中，我们就这些共刺激分子的有前途的治疗效果和潜在的抗肿瘤机制讨论了研究的进展，并综述了可能协同刺激的激动性单克隆抗体与其他治疗黑色素瘤的疗法（包括抑制性免疫检查点单克隆抗体，过继性T细胞疗法，化学疗法和放射疗法）之间相互作用的可能性。我们还简要介绍了这些针对黑色素瘤患者的基于共刺激激动性单克隆抗体的联合策略所涉及的局限性和挑战。