Cancer-associated fibroblasts (CAFs) are abundant and important components of the tumour mesenchyme, and have been extensively studied for their role in primary tumours. CAFs provide biomechanical support for tumour cells and play key roles in immunosuppression and tumour metastasis. CAFs can promote epithelial-mesenchymal transition (EMT) of the primary tumour by secreting extracellular vesicles (EVs), increasing adhesion to tumour cells, remodelling the extracellular matrix (ECM) of the primary tumour, and changing its mechanical stiffness, which provides a pathway for tumour metastasis. Moreover, CAFs can form cell clusters with circulating tumour cells (CTCs) to help them resist blood shear forces and achieve colonisation of distant host organs. Recent studies have revealed their roles in pre-metastatic niche (PMN) formation and prevention. In this review, we discuss the role of CAFs in PMN formation and therapeutic interventions targeting PMN and CAFs to prevent metastasis.

Intermedin (IMD) is a member of calcitonin/calcitonin gene–related peptide family, which shares the receptor system consisting of calcitonin receptor–like receptor (CRLR) and receptor activity–modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro- L -arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N ^ω -propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene–related peptide receptor antagonist calcitonin/calcitonin gene–related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO.

Drug-tolerant persister (DTP) cells drive therapeutic resistance in EGFR-mutant lung adenocarcinoma. Using single-cell RNA sequencing, we identified a clinically significant RGS5+MYL9+ cancer-associated fibroblast (CAF) population that was associated with EGFR tyrosine kinase inhibitor (TKI) resistance and poor prognosis. These CAFs were recruited to DTP niches via CCL11 signaling, and they formed tunneling nanotubes through Miro1/RhoA activation induced by TKI-generated mitochondrial reactive oxygen species. Remarkably, RGS5+MYL9+ CAFs functioned as “metabolic sinks” by accepting tumor-derived damaged mitochondria, thereby promoting DTP survival. Treatment with fasudil, a Rho kinase inhibitor, effectively blocked mitochondrial transfer and restored sensitivity to the EGFR-TKI osimertinib in vivo. Together, this work reveals targetable stromal–tumor cross-talk that sustains DTP populations, proposing a combination therapy for overcoming EGFR-TKI resistance. Significance: Pharmacological blockade of nanotube-mediated mitochondrial transfer between tumor cells and RGS5+MYL9+ fibroblasts effectively overcome tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer, offering a clinically applicable strategy to enhance EGFR inhibitor efficacy.

The limited response rate to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of lung adenocarcinoma (LUAD). In our study, we identified a lactate-based chemical barrier surrounding FAP⁺ cancer-associated fibroblasts (CAFs) within the LUAD microenvironment (TME), which may hinder the infiltration and function of CD8⁺ T cells. Further investigation revealed that FAP⁺ CAFs specifically overexpress LINC01711, which drives lactate production by promoting FGFR1-mediated phosphorylation of lactic dehydrogenase A (LDHA) at the Y10 site and facilitating the formation of active LDHA tetramers. These FAP⁺ CAFs then export lactate into TME via the MCT4 transporter, thereby establishing a chemical barrier and fostering an immunosuppressive TME. Notably, we developed a small extracellular vesicle (sEV)-based in vivo self-assembled siRNA system for in vivo knockdown of LINC01711 and demonstrated its potential to enhance the response rate to ICIs in LUAD. Our findings underscore the pivotal role of FAP⁺ CAFs in driving resistance to ICIs and propose novel therapeutic strategies to overcome this obstacle.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs), especially third‐generation TKIs, have significantly improved the progression‐free survival and overall survival of non‐small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR‐wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR‐mutated patients. EGFR‐mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death‐ligand 1 (PD‐L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR‐mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR‐mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR‐mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.