Cancer-associated fibroblasts (CAFs) are prominent components within the tumor microenvironment (TME) and play significant roles in tumor proliferation and metabolic activity. They exert influences on various aspects of the TME, including tumor cells, immune cells, cytokines, and chemotactic factors. In normal tissues, fibroblasts are typically quiescent as characterized by low metabolic and cell proliferation activities. Nevertheless, they can be activated in response to tissue injury (He et al., 2022). CAFs are known to arise from various cell types in the TME, not limited to traditional fibroblasts and stellate cells. For example, in certain conditions, bone marrow-derived macrophages have been shown to convert into CAFs, contributing to the progression of spontaneous pancreatic ductal adenocarcinoma (PDAC) in mice (Raz et al., 2018, Iwamoto et al., 2021). Similarly, endothelial cells, adipocytes, and pericytes are also capable of transdifferentiating into CAFs under specific conditions (Glabman et al., 2022, Caja et al., 2018, Zhang et al., 2009). CAF populations display diverse capabilities and phenotypes that can promote or inhibit tumor growth. Through the secretion of substances and release of exosomes, CAFs regulate cellular pathways integral to tumor progression (Ozdemir et al., 2014, Rhim et al., 2014). For instance, interleukin-6 (IL-6) secreted by CAFs is involved in extracellular matrix (ECM) remodeling via the JAK-ROCK-STAT3 pathway in melanoma and contributes to chemotherapy resistance through the STAT3/NF-κB pathway in esophageal squamous cell carcinoma (Mao et al., 2021, Qiao et al., 2018, Maharati and Moghbeli, 2023, Mu et al., 2012, Bhowmick et al., 2004). Moreover, stromal cell-derived factor-1 (SDF-1) produced by NRP2+ CAF is linked to chemotherapy resistance through the vascular endothelial growth factor (VEGF)/NRP2 axis, while hypoxia-induced angiogenesis regulator from hypoxic CAFs promotes angiogenesis via the VEGF/VEGFR pathway in breast cancer (BC) (Mu et al., 2012, Bhowmick et al., 2004, Yang et al., 2022a, Kugeratski et al., 2019).

In recent years, neoadjuvant therapy has become an established treatment for cancer. In contrast to adjuvant therapy, neoadjuvant therapy is used prior to surgery in patients diagnosed with tumors. It aims to reduce tumor size, clinical stage, as well as positive surgical margin rates, and provide surgical options for individuals with high-risk or locally advanced inoperable cancers. Additionally, neoadjuvant therapy can be used in combination with targeted therapy or immunotherapy to enhance treatment efficacy, offering a broader range of therapeutic options.

A key mechanism through which neoadjuvant therapy exerts its effects is by promoting immune cell infiltration into the TME. This infiltration assists in activating the immune system and enhancing the body’s ability to combat the tumor (Xing et al., 2022, Ueno et al., 2022, Zhang et al., 2020a, Li et al., 2019, Dang et al., 2019, Simoni et al., 2018, Tumeh et al., 2014, Herbst et al., 2014). Furthermore, neoadjuvant therapy has been shown to mitigate therapeutic resistance to anti-PD-1 therapy by modulating the immune system (Kelly et al., 2018). However, after neoadjuvant therapy, CAFs, the principal constituents of the TME, interact with tumor cells and immune cells by releasing various vesicles and cytokines, such as IL-6, SDF-1 and transforming growth factor-beta (TGF-β) (De et al., 2021). This interaction disrupts immune system regulation and potentially compromises treatment effectiveness (Pei et al., 2023, Barrett and Pure, 2020, De Jaeghere et al., 2019). Numerous studies have identified CAFs as significant mediators of therapeutic resistance (Barrett and Pure, 2020, Mehraj et al., 2021, Saw et al., 2022, Wu et al., 2021, Espinet et al., 2022). Therefore, a comprehensive understanding of how neoadjuvant therapy influences CAFs is crucial for developing novel and more effective treatment strategies utilizing diverse mechanisms.

This review provides an overview of the roles played by CAFs in neoadjuvant settings for solid tumors. Moreover, it summarizes the variations observed in different treatment regimens and the shifts occurring in CAFs within the TME following neoadjuvant therapy.