阐明免疫治疗抗性机制并开发提高效果的策略是具有挑战性的目标。生物信息学分析表明，黑色素瘤中CDK6表达高与接受单一免疫治疗的患者无进展生存率低相关。肿瘤微环境细胞中CDK6或cyclin D3（但不是CDK4、cyclin D1或D2）的消耗抑制肿瘤生长。CDK6消耗重塑肿瘤免疫微环境，宿主抗肿瘤效应取决于cyclin D3/CDK6表达的CD8+和CD4+ T细胞。这是由于CDK6磷酸化并增强PTP1B和T细胞蛋白酪氨酸磷酸酶（TCPTP）的活性，进而减少CD3ζ的酪氨酸磷酸化，降低T细胞激活的信号转导。与使用CDK6降解剂相比，以PTP1B和TCPTP抑制剂为基础的治疗更具效力，有助于增强T细胞介导的免疫治疗。针对蛋白酪氨酸磷酸酶（PTP）可能是治疗抗免疫治疗癌症患者的有效策略。 Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Elucidating the mechanisms of resistance to immunotherapy and developing strategies to improve its efficacy are challenging goals. Bioinformatics analysis demonstrates that high CDK6 expression in melanoma is associated with poor progression-free survival of patients receiving single-agent immunotherapy. Depletion of CDK6 or cyclin D3 (but not of CDK4, cyclin D1, or D2) in cells of the tumor microenvironment inhibits tumor growth. CDK6 depletion reshapes the tumor immune microenvironment, and the host anti-tumor effect depends on cyclin D3/CDK6-expressing CD8+ and CD4+ T cells. This occurs by CDK6 phosphorylating and increasing the activities of PTP1B and T cell protein tyrosine phosphatase (TCPTP), which, in turn, decreases tyrosine phosphorylation of CD3ζ, reducing the signal transduction for T cell activation. Administration of a PTP1B and TCPTP inhibitor prove more efficacious than using a CDK6 degrader in enhancing T cell-mediated immunotherapy. Targeting protein tyrosine phosphatases (PTPs) might be an effective strategy for cancer patients who resist immunotherapy treatment.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.