Exploring new frontiers in lung cancer treatment: The role of cancer-associated fibroblasts (CAFs) and EGFR-TKI resistance

Abstract

Lung cancer is the malignant tumour with the highest global morbidity and mortality rates, and a substantial proportion of lung cancers are driven by EGFR mutations.^{1, 2} EGFR tyrosine kinase inhibitors (EGFR-TKIs) can specifically bind to mutated EGFR proteins, blocking the carcinogenic process, and have thus become the preferred treatment for patients with EGFR-mutation-positive lung cancer.³

However, despite the remarkable efficacy of EGFR-TKIs in the initial treatment phase, patients often experience tumour progression due to drug resistance after 10–20 months.⁴ This highlights the importance of identifying new therapeutic targets to enhance the efficacy of EGFR-TKIs. Currently, the combination of immune checkpoint inhibitors or traditional chemotherapy with EGFR-TKIs offers limited benefits for patients' long-term survival, underscoring the urgent need to explore new therapeutic targets.³

The strategy for cancer treatment has shifted from solely targeting tumour cells to also focusing on modulating the tumour microenvironment. Cancer-associated fibroblasts (CAFs), one of the most abundant stromal components in the tumour microenvironment, have been observed to infiltrate and invade the areas where lung cancer cells retreat in the cancer nest during EGFR-TKI treatment, surrounding the residual lung cancer cells. This suggests that CAFs may play a crucial role in EGFR-TKI resistance.^{5, 6}

In terms of cellular origin, CAFs are a complex collection of multiple cell subsets, mainly including normal tissue fibroblasts induced and activated in the tumour microenvironment (TME), bone marrow-derived fibroblasts and mesenchymal stem cells recruited and migrated to the TME, and stromal cells (such as epithelial cells, endothelial cells, and smooth muscle cells) that can undergo transdifferentiation under specific conditions.^{7, 8} The diversity of cellular origins and the intricate interactions between CAFs and tumour cells, as well as other non-tumour cells, contribute to the wide range of phenotypic and functional heterogeneity exhibited by CAFs.^{9, 10}

The research by Xu et al. significantly advanced our understanding of lung cancer by identifying a unique CAFs subset marked by the co-expression of CXCL14 and POSTN (CXCL14 + POSTN + CAFs).¹¹ The authors further demonstrated that CXCL14 + POSTN + CAFs promote metastasis through epithelial-mesenchymal transition (EMT) and angiogenesis and have a specific association with EGFR-TKI resistance. This subset-specific resistance may stem from paracrine signalling (CXCL14 secreted by CAFs activates STAT3 in cancer cells through CXCR4, bypassing EGFR blockade) and the matrix barrier (the extracellular matrix rich in POSTN may physically impede drug penetration).

In addition, Xu et al.’s identification of Filgotinib (an FDA-approved JAK1 inhibitor) as a CAFs-targeting agent represents a significant translational advance.¹¹ By resensitizing EGFR-TKI-resistant tumours in organoid co-culture and xenograft models, this study highlights its potential to overcome matrix-driven resistance. The use of patient-derived samples and the correlation with EGFR-TKI outcomes underscore its clinical significance.

The work of Xu et al. showcases the power of integrating stromal biology into cancer treatment¹¹. By identifying CXCL14 + POSTN + CAFs as an actionable target, they have paved the way for precision strategies that go beyond traditional genetic stratification¹¹. However, realizing this potential requires multidisciplinary efforts, combining high-resolution single-cell analysis, robust biomarker validation, and innovative clinical trial design. As the field moves towards “ecosystem-targeted therapy,” such research reminds us that cancer is a complex ecosystem where the stroma and tumour cells co-evolve under the influence of drugs, bringing new hopes and challenges for cancer treatment.

Jiaqi Liang and Yidu Hu wrote the initial draft of this manuscript. Cheng Zhan reviewed the manuscript. All authors approved the final version of this review.

The authors declare no conflicts of interest.

The authors have nothing to report.