Advanced non-small cell lung cancer (NSCLC) continues to be an incurable family of thoracic malignancies that is chronically managed with chemotherapy, targeted therapy, and immunotherapy. While the discovery of driver oncogenes and the advent of targeted and immunotherapies in the last decade have vastly improved clinical disease management for patients harboring druggable mutations, the mainstay treatment for the majority of NSCLC patients remains cytotoxic chemotherapy. The clinical efficacy of targeted, immune, and cytotoxic therapies is limited by the development of drug resistance. Transforming growth factor beta (TGFβ) signaling, a crucial mediator of embryonic development and peripheral immune tolerance, may be dysregulated in some malignant contexts, including lung cancer, and has been correlated with poor prognosis in advanced cancers. Aberrant upregulation of TGFβ expression in the tumor microenvironment has also been implicated in promoting NSCLC progression and metastasis, as well as driving the development of resistance to cytotoxic, targeted, and immunomodulatory therapeutic interventions. Here, we examine the mechanisms underlying TGFβ-mediated drug resistance in NSCLC, and consider TGFβ as a combinatorial therapeutic intervention to circumvent or delay the development of NSCLC treatment resistance.

晚期非小细胞肺癌（NSCLC）仍然是不可治愈的胸部恶性肿瘤家族，可通过化学疗法，靶向疗法和免疫疗法进行长期管理。尽管在过去十年中发现了驱动癌基因以及靶向和免疫疗法的出现大大改善了可携带药物突变患者的临床疾病管理，但大多数非小细胞肺癌患者的主要治疗手段仍然是细胞毒性化学疗法。靶向，免疫和细胞毒性疗法的临床疗效受到耐药性发展的限制。转化生长因子β（TGFβ）信号传导是胚胎发育和外周免疫耐受的关键介质，在包括肺癌在内的某些恶性环境中可能失调，并且与晚期癌症的不良预后相关。肿瘤微环境中TGFβ表达的异常上调也与促进NSCLC进展和转移以及驱动对细胞毒，靶向和免疫调节治疗干预的耐药性有关。在这里，我们检查了非小细胞肺癌中TGFβ介导的耐药性的机制，并考虑将TGFβ作为一种组合治疗干预措施来规避或延迟NSCLC治疗耐药性的发展。