These CAFs play a pivotal role in the recruitment and polarization of inflammatory cells (Fig. 1A). Chemokines secreted by both tumor cells and CAFs facilitate the infiltration of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and lymphocytes into the TME, thus intensifying the inflammatory response (28,29). CAFs contribute to macrophage recruitment by secreting pro-inflammatory cytokines such as IL-1β and IL-6, along with C-X-C motif chemokine ligand (CXCL)1 and −2, exerting these effects even in the absence of tumor cells (30). Furthermore, CAFs produce extra domain A fibronectin variants that bind to macrophage Toll-like receptor 4, consequently inducing M2 macrophage polarization (31). In hepatocellular carcinoma (HCC), cardiotrophin-like cytokine factor 1 secreted by CAFs enhances the production of chemokine ligands CXCL6 and TGF-β in tumor cells, thus promoting tumor cell stemness through an autocrine mechanism while facilitating TAN infiltration and polarization via paracrine signaling (32). In lung cancer, CAFs secrete CCL2 and CXCL12, which mediate the recruitment of monocytes and promote their differentiation into myeloid-derived suppressor cells (MDSCs), thus suppressing CD8+ T-cell proliferation and interferon-γ (IFNγ) production (33). In addition, hyaluronic acid (HA)-producing CAFs interact with MDSCs and epithelial tumor cells, leading to HA degradation and the accumulation of pro-inflammatory HA fragments, further exacerbating cancer-associated inflammation. The HA-rich stromal environment promotes the differentiation of tumor-infiltrating hyaluronan 2+ MDSCs into programmed death ligand 1 (PD-L1)+ TAMs, thus establishing an immunosuppressive and tumor-favorable TME (34).

CAFs play a crucial role in the secretion of inflammatory mediators (Fig. 1B). In response to various stimuli, CAFs directly produce pro-inflammatory cytokines, IL-6, IL-1β, IL-11, leukemia inhibitory factor (LIF) and TGF-β, contributing to tumor-associated inflammation. They can also recognize damage-associated molecular patterns and activate the NOD-, LRR- and pyrin domain-containing protein 3 inflammasome pathway, leading to the induction of pro-inflammatory signaling and the secretion of IL-1β (35). IL-1 binds to its receptor to activate the NF-κB signaling pathway, exerting crucial functions in regulating innate immunity and inflammation (36). A study identified fibroblasts that sustain the activation of STAT3 through the urokinase-type plasminogen activator receptor (uPAR)-dependent focal adhesion kinase (FAK)-Src-JAK2 signaling cascade. Further, uPAR-dependent FAK-Src-JAK2 signaling within tumor-associated fibroblasts regulated the inflammatory component of the TME in a liver cancer model (37). CAFs-secreted IL-1, IL-6 and IL-22 can activate STAT3 signaling and promote the development of inflammation in tumors (38–40). In particular, IL-6 acts as a stromal messenger, triggering JAK/STAT3 and TGFβ signaling in malignant cells to enhance invasion and induce epithelial-to-mesenchymal transition (EMT) (38,41). Tumor and immune cells within the TME can also activate CAFs through paracrine signaling, inducing the production of cytokines and chemokines. Even normal dermal fibroblasts can be affected by cancer cells to upregulate pro-inflammatory gene expression (30). IL-1α and IL-1β released by pancreatic cancer cells and TAMs are key regulators of thymic stromal lymphopoietin (TSLP) secretion by CAFs. This secretion is pivotal in facilitating TSLP-mediated modulation of type 2 T-helper cell immune responses (42). The paracrine inflammatory mediator TNF-α, originating from immune cells or tumor cells, induced CAFs to express IL-6 and chemokine CCL2 in colorectal metastatic and liver metastatic cancers, along with pro-angiogenic CXCL8/IL-8 expression in an NF-κB-dependent manner (43–45). Meanwhile, CAFs possess the ability to undergo self-activation through autocrine signaling. In breast cancer, TGF-β and stromal cell-derived factor (SDF)-1α/CXCL12 secreted by CAFs initiate autocrine signaling loops that maintain their differentiation and tumor-promoting phenotypes. However, the specific in vivo molecular signals that activate these inflammatory pathways in CAFs remain unidentified (46).

CAFs are the main cellular components of the stroma and are the primary source of connective tissue and proteolytic enzymes within the ECM (Fig. 1C). The production of ECM by CAFs modifies and engages multiple signaling pathways from the cell surface to the nucleus, resulting in alterations in gene expression and cellular behavior. CAFs promote ECM degradation and remodeling by secreting cytokines, chemokines and other effector molecules (TGF-β, CXCL2), various matrix proteins (fibronectin and type I collagen) and MMPs (47,48). ECM deposition is intricately associated with TGF-β, a relationship mediated by CAFs through the production of activin A, which promotes epithelial cell migration and induces EMT (49). These fibroblasts synthesize significant amounts of laminin, which binds to α6β4 integrin receptors on malignant cells, thus enhancing their migration potential (50). They are also the primary source of HA, a crucial stromal-derived component that facilitates the recruitment of TAMs, which are predominantly concentrated within the HA-rich tumor stroma (51). A single-cell RNA-sequencing study revealed that CAFs interact with a tumor-specific keratinocyte subpopulation that shows significant EMT features, with the pleiotropic growth factor Midkine being upregulated in primary CAFs (52).

The ECM is a crucial component of the TME, providing structural support and regulating the microenvironment and cellular interactions. Changes in its composition, density and rigidity are closely associated with tumor progression. Increased ECM rigidity influences cellular behavior by altering mechanotransduction pathways, thus affecting the capacity of cells to perceive and respond to external mechanical stimuli. The ECM also activates T cells and promotes their differentiation through integrin-mediated complexes to regulate immune cells (53). TGF-β plays a significant role in regulating ECM stiffness, while MMPs promote ECM degradation and remodeling, both of which are essential for tumor cell invasion. TGF-β is predominantly secreted and deposited within the ECM as latent complexes (54). Pathological upregulation of TGF-β induces EMT, promotes ECM deposition and drives the activation of CAFs, ultimately contributing to fibrotic diseases and cancer progression (16). MMP is the most relevant protease for primary tumors, regulating various physiological processes and signal transduction events (55). The most well-known function of MMP is to cleave ECM proteins to regulate ECM remodeling. Certain hydrolyzed protein fragments of the ECM are chemotactic, recruiting neutrophils, increasing their chemotactic activity and exacerbating tumor inflammatory responses (56). The interaction between the tumor and ECM activates the Notch1 pathway through pro-inflammatory signaling, leading to the induction of CXCL8, which promotes tumor metastasis (57). Several proteins associated with inflammation, stromal remodeling, TGF-β receptor signaling and angiogenesis have been identified within the stromal microenvironment (58).

Inflammatory fibroblasts (iCAFs) exhibit hypoxia-associated gene expression and biochemical profiles. These cells are predominantly localized in hypoxic regions of pancreatic cancer, whereas myofibroblasts (myCAFs) are largely absent. Hypoxia further enhances cytokine-induced iCAF phenotypes, contributing to tumor progression (59). The transcriptional target of hypoxia-inducible factor (HIF)-1α, the G-protein estrogen receptor, establishes a feed-forward loop in which IL-1β secretion by fibroblasts enhances IL1R1 expression in breast cancer cells. Furthermore, IL-1β present in the conditioned medium of triple-negative breast cancer cells under hypoxic conditions reinforces the invasion of fibroblasts (Fig. 1D) (60). MyCAFs deficient in caveolin-1 activate HIF and NF-κB transcription factors, generating oxidative stress that promotes aerobic glycolysis and inflammation, thus creating a pseudo-hypoxic state. This phenomenon drives the ‘reverse Warburg effect’ within the TME, where aerobic glycolysis occurs predominantly in tumor-associated fibroblasts rather than malignant cells, facilitating metastasis (61,62). The lactate-NAD+ axis further activates CAFs by downregulating p62, which enhances tumorigenesis through inflammation and metabolic reprogramming in both in vitro and in vivo models (63). Furthermore, the dense ECM exerts mechanical pressure on blood vessels, inducing hypoxia, with collagen deposition contributing to the expression of hypoxia-related aberrant factors (64).

The association between hypoxia and inflammation is well established, with inflammatory diseases frequently showing severe hypoxic conditions. Malignant tumor cell clones consume substantial amounts of oxygen, inducing persistent hypoxia that sustains chronic inflammation. This process is driven by the release of reactive oxygen species (ROS) and nitric oxide alongside NF-κB activation, which plays a pivotal role in the induction of HIF. Elevated levels of HIF further promote the production of multiple pro-inflammatory mediators, reinforcing the inflammatory state within the TME (65,66). HIF-1α can interact with p53 to inhibit its activity, thus reducing p53-induced apoptosis and promoting tumor cell survival and metastasis (67). The inactivation of the tumor suppressor p53 results in the upregulation of NF-κB, a key positive regulator of inflammatory signaling, thus fostering a pro-inflammatory microenvironment conducive to tumor metastasis (68). HIF-1α modulates various immune functions, including the polarization of M1 macrophages, the maturation and migration of dendritic cells, and the formation and survival of neutrophil extracellular traps. In comparison, another transcription factor, HIF-2α, promotes M2 macrophage polarization by inducing the expression of M2-associated markers, e.g., arginase 1 (69). HIF-1α has been shown to influence the differentiation and function of different T-cell subsets under both hypoxic and normoxic conditions (70,71). HIF-2α is also expressed in TAMs and its depletion in TAMs impairs the expression of chemokine receptors and the migration and infiltration of TAMs (69).

Cellular senescence is characterized by progressive mitochondrial dysfunction, resulting in elevated production of ROS, such as H₂O₂, which increases the risk of carcinogenesis (72). Studies suggest that alterations in senescence-associated secretory phenotype (SASP) gene expression in senescent CAFs facilitate malignant tumor proliferation (73). In tumor tissues, H₂O₂-activated CAFs interact with tumor cells to produce H₂O₂, mimicking the behavior of immune cells like macrophages and neutrophils, driving local and systemic inflammation through the innate immune response, mainly via NF-κB activation (Fig. 1E) (74). Pro-inflammatory cytokines mediate the epigenetic modification of H3K27me3 in CAFs, thus sustaining the SASP and promoting peritoneal tumor formation in gastric cancer by activating the JAK/STAT3 signaling pathway (75).

Cellular senescence is distinguished by a reduced proliferative potential, the activation of anti-apoptotic pathways and the secretion of pro-inflammatory cytokines, chemokines and interleukins (IL-6, IL-1α and IL-1β). It also involves releasing growth factors, proteases and their inhibitors, angiogenic factors and insoluble components (fibronectin, collagen and laminin). Other inflammatory mediators, including growth differentiation factor-15, TGFβ1 and IFNγ, also contribute to this secretory profile, collectively called the SASP (76). Senescent cells demonstrate high oxidative metabolism and ROS production (76). The complex interaction among the SASP, oxidative stress and inflammation highlights the intrinsic association between cellular senescence and the initiation and progressive accumulation of inflammatory responses (77).

MyCAFs originate from various cell types, including fibroblasts, smooth muscle cells and epithelial cells. Their activation is primarily driven by inflammatory signals and tissue injury (Fig. 2A). These cells functionally resemble contractile fibroblasts involved in wound healing. TGF-β is a key regulator of myCAF differentiation, inducing their activation from multiple cell types. Upon activation, TGF-β binds to its receptor, leading to the phosphorylation of Smad2/3, which then form a complex with Smad4 and translocate into the nucleus to regulate gene transcription (12); TGF-β promotes CAF formation primarily through the Smad-dependent signaling pathway, where Smad2/3 phosphorylation leads to CAF differentiation with high expression of αSMA and SDF1/CXCL12 (79–81). The upregulation of microRNA-21 (miR-21) in CAFs, mediated by the TGF-β signaling pathway, enhances their CAF-like morphology and migratory capacity (82). Smad7, a negative feedback regulator that antagonizes receptor/Smad signaling, plays a complementary role in modulating this pathway. Either depletion of Smad7 or increased expression of miR-21 contributes to the sustained activation of CAFs, ultimately promoting tumor progression (82). The EMT process with increased expression of FAP, α-SMA and vimentin, primarily driven by TGF-β, further facilitates the differentiation of myCAFs, contributing to fibrosis and metastasis (83,84). In addition to Smad signaling, TGF-β activates non-Smad pathways, including PI3K/AKT and MAPK/ERK, which collectively control fibroblast proliferation, contractility and ECM deposition (85). Furthermore, macrophage recruitment can activate hematopoietic stem cells, maintained by TNF and IL-1, which promote myCAFs activation via ROS and NF-κB-dependent pathways (39,86). MyCAFs are contractile and ECM-remodeling cells that highly express αSMA, transgelin, periostin and collagen-related genes (21). They play a crucial role in modulating the mechanical and structural properties of the tumor stroma. By promoting desmoplasia, myCAFs increase tissue stiffness and contribute to the formation of a dense ECM that acts as a physical barrier, thereby limiting immune cell infiltration and reducing the efficacy of drug delivery.

Compared to myCAFs, iCAFs are directly activated by pro-inflammatory cytokines (Fig. 2A). TNFα and IL-1 play a central role in the activation mechanism of iCAFs. These cytokines promote the transformation of mesenchymal stem cells (MSCs) and pancreatic stellate cells into iCAFs, characterized by elevated expression of FAP, reduced αSMA levels, enhanced proliferative capacity and upregulated expression of CCR2, CCR5 and CXCR1/2 (8,87). TNFα, secreted by neutrophils, binds to TNFR2 on the cell membrane, leading to the overproduction of CXCL1, a feedforward factor that polarizes iCAFs and induces T-cell dysfunction (88). Similarly, IL-1β signaling through the P53/NF-κB pathway results in the secretion of IL-6, which activates CAF-tumor cell IL-6/STAT3 signaling pathways, further enhancing the inflammatory CAF phenotype (9,89). ICAFs secrete high levels of inflammatory cytokines and chemokines, such as IL-6, IL-11, CXCL1, CCL2 and LIF, which can recruit immunosuppressive cells, promoting tumor-associated inflammation (21).

Growing evidence suggests that the IL-6/STAT3 and TGF-β signaling pathways interact synergistically, forming a positive feedback loop that sustains inflammation-driven activation of CAF. IL-6, a pro-inflammatory cytokine, activates the JAK/STAT3 pathway, which in turn enhances TGF-β signaling by promoting the phosphorylation of Smad3, a key mediator of TGF-β-induced transcriptional responses (90). Treatment with IL-6 increased the expression of TGF-β type I receptor in A549, NCI-H358 and NHLF cells, thus enhancing TGF-β signaling and fibroblast activation (91). However, certain findings indicate that the simultaneous presence of cytokines may lead to TGF-β-mediated suppression of IL-6-induced proliferative effects, highlighting more intricate regulatory dynamics (92,93).

The immunosuppressive properties of CAFs are modulated by inflammatory signaling cascades, cytokines and chemokines (Fig. 2B). IL-6 and TGF-β are crucial mediators through which CAFs suppress cytotoxic T lymphocyte infiltration, and blocking IL-6 has been shown to enhance T-cell function (94,95). The CXCL12-CXCR4 signaling axis promotes the interaction between CAFs and monocytes, inducing the reprogramming of monocytes into an immunosuppressive phenotype (96). Furthermore, CAFs also promote the recruitment of monocytes and their differentiation into M2-TAMs by secreting IL-8, IL-10, TGF-β and CCL2, thus impairing effector T-cell responses and inducing immunosuppression within the TME (97). CAFs also mediate neutrophil chemotaxis and activation of TANs through the IL-6/STAT3/ERK1/2 axis (98). IL-6 stimulation activates the STAT3 signaling pathway in TANs, suppressing T-cell activity and inducing immune tolerance via PD-L1 expression (99). In melanoma and colorectal cancer, CXCL5 facilitates the upregulation of PD-L1 expression on tumor cells via a PI3K/AKT-dependent mechanism, thus enhancing immune tolerance and promoting tumor immune evasion (100).

Inflammation is pivotal in enhancing the invasive properties of CAFs (Fig. 2C). Exposure of breast cancer cells to TNFα or IL-1β, in co-culture with MSCs or CAFs, leads to a significant upregulation of CXCL8, CCL2 and CCL5 expression. This observation underscores the contribution of tumor-stroma-inflammation interactions in driving tumor aggressiveness (57,101). M2-type macrophages can also drive EMT progression by secreting soluble factors such as IL-6 and SDF-1 (102). In vitro co-culture studies analyzing the interaction between TAMs and CAFs have revealed that macrophages significantly enhance the invasive potential of both tumor cells and CAFs (103). Similarly, TANs secrete VEGF, CCL17 and MMP9, which induce tumor angiogenesis, remodel the ECM in the TME and promote tumor invasion and metastasis (104). Inflammation-activated iCAFs show elevated expression of inflammatory genes and chemokines, facilitating tumor metastasis by activating Ras and GαI proteins (8). Inhibition of the Notch1-Jagged1/NF-κB (p65) signaling pathway downregulates key factors associated with CAF activity, leading to ECM remodeling and reduced tumor metastasis, even under TNF-α stimulation (105). Similarly, knockout of the G protein-coupled receptor 30 suppresses IL-6 secretion and attenuates the invasive potential of CAFs (106).

The ECM, comprising structural components such as collagen and HA, plays a pivotal role in tumor chemoresistance by establishing a dense matrix that serves as a physical barrier, thus hindering the effective penetration of therapeutic agents (107). CAFs contribute to this resistance by secreting cytokines, chemokines, growth factors and exosomes, which engage their respective signaling pathways, ultimately protecting cancer cells from apoptosis induced by therapeutic interventions (Fig. 2D).

Inflammation plays a crucial role in tumor formation. During tumor treatment, a reduction in the neutrophil-to-lymphocyte ratio induces the reprogramming of iCAFs, leading to a marked decrease in IL-6/STAT-3 expression and enhancing chemotherapy sensitivity in preclinical models of pancreatic cancer (9). Hypoxia within the TME, driven by COX-2 secretion from CAFs, M2 macrophages and cancer cells, and its positive interaction with Yes-associated protein 1 and anti-apoptotic mediators, fosters cancer cell resistance to chemotherapy (14). Furthermore, exosomal miRNA-20a secreted by CAFs inhibits the phosphatase and tensin homolog/PI3K-AKT pathway, promoting non-small cell lung cancer progression and inducing resistance to cisplatin (108).