CAFs are activated fibroblast populations and the major cellular components of the TME in primary and metastatic cancers ^[5][6][26,27]. CAFs have different features from normal fibroblasts after infiltrating tumor tissue, such as enhanced proliferation and epigenetic changes to produce secreted factors ^[7][28]. CAFs are contributors to desmoplasia that can facilitate tumorigenicity, cancer cell proliferation, metastasis, and cancer immunotherapy resistance through complex interactions and intricate signaling ^[8][29] with other cell types in the TME ^[9][30].

The population of CAFs are highly heterogeneous because several progenitor cell types can be reprogrammed into CAFs ^[10][31]. Quiescent or resident fibroblasts are major progenitor cells of CAFs ^[11][32]. Hepatic ^[12][33] or pancreatic stellate cells ^[13][34] are the putative origin of CAFs. Adipocytes ^[14][35], endothelial cells ^[15][36], epithelial cells ^[16][37], and bone marrow cells ^[17][38] can be reprogrammed into CAFs. CAFs can also derive from multiple resident precursors, such as smooth muscle cells or mesenchymal stem cells ^[18][39]. Nevertheless, the precise origins of CAFs remain elusive because of the lack of lineage biomarkers.

CAFs have both tumor-promoting and tumor-suppressive functions ^[19][40]. The tumor-suppressive functions of CAFs ^[20][41] remain poorly understood. Part of the host defensive mechanism involves promotion of anticancer immunity, tumor-inhibitory signaling, tumor-restraining metabolism, and ECM-related physical barriers to tumor cell invasion and dissemination. Desmoplasia is the growth of fibrous or connective tissue in desmoplastic breast, lung, and pancreatic cancers. The desmoplastic reaction may form the desmoplasia or dense fibrosis around the tumor to restrict its growth and migration ^[21][42]. The mechanisms of tumor-promoting roles of CAFs are mainly regulatory functions via growth factors, cytokines, and chemokines contributing to angiogenesis; ECM remodeling; aberrant stroma, and an immunosuppressive TME ^[22][43]. Mass cytometry and single-cell analysis of pancreatic tumors and healthy pancreas samples found two stable and functionally distinct pancreatic fibroblast lineages. CD105-positive pancreatic fibroblasts promote tumor growth, but CD105-negative fibroblasts are highly tumor suppressive in a manner dependent on adaptive immunity ^[23][44].

CAF subsets have specialized secretory functions, such as cytokines, chemokines, and ECM molecules collagen I, which contribute to ECM remodeling and immunomodulatory function. Tumor–fibroblast interactions via soluble factors determine the final outcome of the tumorigenic process and affect the cancer therapy ^[24][45]. The CAF population is heterogeneous according to the cell origins, and the functional heterogeneity can be regulated by paracrine molecules such as CXCL8 and CXCR1/2 ligands ^[9][30]. CAFs can attract monocytes by secreting CXCL8 to enhance TAM enrichment and suppress NK cells’ function in colorectal cancer ^[25][46]. In gastric cancer tissues of chemoresistant patients, CXCL8 was highly expressed and located in CAFs by immunohistochemistry assay. A high serum CXCL8 level was associated with poor response to cisplatin therapy in gastric cancer patients ^[26][47]. CAFs are major sources of chemokines (CXCL1 and CXCL8) that recruit granulocytes (TAM and PMN-MDSC) to tumors. Combining a selective CSF1R inhibitor (JNJ-40346527) with a CXCR2 antagonist (SB225002) blocked granulocyte recruitment and demonstrated a strong antitumor effect, which was further improved by the addition of antiprogrammed cell death protein 1 (PD-1) ^[27][48].

Chronic inflammation and proinflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) can induce the conversion of MSCs to inflammatory CAFs. These CAFs secrete prometastatic chemokines including CXCL6 and CXCL8 in Luminal-A breast cancer cells and enhance migration ^[28][49]. CXCL8 can induce normal ovarian fibroblasts to CAFs and stimulate xenograft tumor growth in mice. The ovarian cancer cell stemness was promoted by the CXCL8 secreted from CAFs through the Notch3 signaling pathway ^[29][50]. Gastric cancer extracellular vesicles transfer various miRNAs and induce chemokines such as CXCL1 and CXCL8 expression in CAFs. Aberrant chemokine CXCL1 and CXCL8 expression in CAFs was closely associated with tumor progression and poorer survival in gastric cancer patients ^[30][51]. CAFs demonstrate a high level of basal secretory autophagy in head and neck squamous cell carcinoma. Secretory autophagy is involved in the export of cellular inflammatory mediators such as IL-6 and CXCL8. Combination therapy using autophagy inhibition with cisplatin significantly reduced tumor volume ^[31][52].

Stromal cells such as CAFs and MSCs enhance the triple-negative subtype of breast cancer metastasis-related phenotypes, including angiogenesis, migratory, and invasive properties, by releasing inflammatory chemokines such as CCL2 and CXCL8 ^[32][53]. Notch 1 activation is required for the induction of CXCL8 in tumor–stroma interactions and consequently for prometastatic activities ^[33][54]. Androgen receptor signaling in CAFs affects prostate cancer cell migration mediated by CXCL8 and CCL2 ^[34][55]. CAFs express CXCR2 and respond to paracrine signals of pancreatic cancer cells by upregulating CXCR2 ligands such as CXCL1, CXCL7, and CXCL8. CXCR2 knockout in a pancreatic ductal adenocarcinoma syngeneic mouse model suppressed angiogenesis and induced an antitumor response, but increased CAF activation, fibrosis, and metastasis in a mutation-dependent manner ^[35][56].

The CAF response to chemotherapy is highly variable and may impact on cancer therapy outcome ^[36][57]. Traditional maximum-tolerated dose chemotherapy induces CAF activation and results in the expression and secretion of ELR motif-positive chemokines such as CXCL6 and CXCL8 ^[37][58]. These chemokines signal though CXCR2 on cancer cells to transform into tumor-initiating cells, thus promoting aggression and treatment resistance. While the same overall dose administered as a low-dose metronomic chemotherapy largely prevented CAF activation and enhanced treatment response, it improved survival in mice ^[37][58]. CAF-secreted IL-6 and CXCL8 induce Bromodomain-containing protein 4 (BRD4) protein expression and lead to chromatin remodeling and Bromodomain and Extraterminal (BET) inhibitor resistance in colorectal cancer (CRC). Inhibition of IL-6/CXCL8-JAK2 signaling sensitized BET inhibitors in a CRC mouse xenograft model ^[38][59]. Simultaneous blocking of IL-6 and CXCL8 can inhibit CAF-induced human melanoma cell invasiveness using neutralizing antibodies in a 3D spheroid invasion assay ^[39][60]. Senescent human fibroblasts can secrete IL-6 and CXCL8 to promote cancer cell invasion and metastasis ^[40][61]. Senescent CAFs are a pathologically relevant fibroblast population that secrete excess CXCL8 to promote pancreatic cancer invasion ^[41][62]. A new subset of CD10⁺GPR77⁺CAFs induce cancer stem cells’ (CSCs) enrichment and chemoresistance by secreting IL-6 and CXCL8 in cancer. CD10⁺GPR77⁺CAFs constitute a supporting niche for CSCs, and its high expression correlates with poor survival in breast and lung cancer patients ^[42][63].