{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:30:36Z","timestamp":1786696236177,"version":"build-2736575974"},"reference-count":125,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cRongPiao\u201d innovated Program of Chengdu","award":["TJZ20244902"],"award-info":[{"award-number":["TJZ20244902"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Traditional inhibitors of cyclin-dependent kinases 4 and 6 (CDK4\/6) have long been characterized as classical antiproliferative agents that induce G1 cell cycle arrest by blocking the phosphorylation of the retinoblastoma protein (Rb). However, recent studies in lung cancer have expanded this paradigm, revealing a functional transition from exclusive tumor suppression to the profound remodeling of the tumor microenvironment (TME) to enhance antitumor immunity. This review systematically outlines the genomic aberrations of the CDK4\/6-Rb axis across lung cancer subtypes and dissects its immunomodulatory networks. These encompass the activation of effector T cells, the alleviation of immunosuppression mediated by regulatory T cells (Tregs), and the enhancement of antigen presentation via the Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Furthermore, we analyze acquired resistance mechanisms, primarily focusing on p21-CDK2 bypass activation mediated by Cyclin E1 gene (CCNE1) amplification and tumor protein 53 gene (TP53) mutations. We also review clinical investigations combining CDK4\/6 inhibitors with targeted therapies against driver genes, as well as immune checkpoint inhibitors in lung cancer. Notably, in the context of lung cancer, these combinatorial strategies have been primarily investigated in the second-line or subsequent settings following progression on standard platinum-based chemotherapy or immunotherapy. Finally, we propose individualized, stratified treatment strategies based on genomic and immunological biomarkers, providing a translational framework for overcoming multidrug resistance and optimizing next-generation combinatorial regimens in lung cancer.<\/jats:p>","DOI":"10.3390\/ijms27167119","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T09:24:53Z","timestamp":1786353893000},"page":"7119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rewiring the Molecular Interplay of CDK4\/6 Inhibitors in Lung Cancer: From Cell Cycle Control to Immune Microenvironment Remodeling"],"prefix":"10.3390","volume":"27","author":[{"given":"Yin","family":"Ku","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peichuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6996-9819","authenticated-orcid":false,"given":"Yaohui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery and Institute of Thoracic Oncology, West China Hospital, Sichuan University, No.37, Guoxue Valley, Wuhou District, Chengdu 610041, China"},{"name":"Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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