Inflammation is a key part of tumor development, progression, and metastasis. Inflammation is a part of the host defensive mechanism aimed at eliminating harmful pathogens or toxins. Dysregulated chronic inflammation in the tumor microenvironment (TME) contributes to carcinogenesis [1], [2]. Amongst different cancers, pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and ranks sixth in global mortality. PDAC is expected to become the second leading cause of cancer-associated deaths in the U.S.A. by 2030 [3], [4], [5]. PDAC has hallmarks of desmoplastic stroma propensity to metastasis, and resistance to therapies [6], [7], [8]. The high incidence of oncogenic KRAS mutations and the growth of a complex PDAC-TME with various types of cells contribute to the severity and poor treatment responses [9]. The intercommunication between tumor cells, cancer-associated fibroblasts (CAFs), and tumor-associated immune cells is largely driven by secreted pivotal chemical messengers called cytokines [10], [11], [12]. These small signaling molecules induce stromal changes at TME and regulate PDAC establishment and growth. Cytokine signaling intercommunication is central to the establishment of PDAC pathogenesis, which initiates with the crucial step of pancreatic acinar cells transformation into ductal metaplasia and secretion of various types of cytokines by tumor, stromal, and immune cells [13], [14], [15], [16]. Further, these cytokines function as growth factors, helping PDAC invasion and metastasis. The continuous production of various cytokines such as IFN-γ (Interferon gamma), TNF-α (Tumor necrosis factor alpha), IL-1β (Interleukin-1 beta), IL-10 (Interleukin 10), TGF-β (Transforming Growth Factor Beta), and CCL5 (Chemokine (C-C motif) ligand 5) by tumor cells, CAFs (Cancer-associated fibroblast) and tumor-promoting macrophages contributes to the development of immunosuppressive dense environments that cover tumor cells from immune outbreaks and further enhance immune evasion and tumor cell growth [17], [18], [19], [20]. Previous reports suggested that, cytokines plays pivotal role in several cancer hallmark process along with immune cell infiltration/activation. These hallmarks include angiogenesis, chronic inflammation, and metastasis. Additionally, these cellular processes are known to be interconnected within the TME. Together, this phenomenon helps in creating a pro-tumor rich environment that helps in inflammatory cascades and increases metastatic spread via cytokine-mediated signaling [21]. Recent reports suggested that, inhibition of TGF- β signaling with galunisertib in combination with gemcitabine increased the survival benefits in PDAC patients [22]. Similarly, all-trans retinoic acid (ATRA) in combination with chemotherapy also increased survival by modulating PSCs and cytokine signaling in the TME [23]. Thus, it is essential to unravel the molecular mechanism associated with these pivotal cytokine-signaling networks, and it is important to develop target therapies to improve PDAC outcomes and drug resistance.

The cytokine signaling cross talks are central to PDAC tumor cell migration, metastasis, and therapy resistance [24], [25]. Cytokines signaling plays pivotal role within the TME that integrate tumor, stroma, and immune compartments, promote tumor cell growth, and maintain immunosuppressive environments [25], [26]. Stromal cells, particularly CAFs derived from pancreatic stellate cells (PSCs), mainly influence desmoplasia, a characteristic feature of PDAC microenvironment [27], [28], [29]. The strong and mutual communication between tumor and stromal compartments is disparagingly regulated by cytokines secreted from both tumor and stromal cells of the microenvironment [13], [30]. These tumor-promoting inflammatory cytokines IL-1α, IL-6, are produced from oncogenic activated tumor cells, activate crucial cellular signaling pathways like STAT3 and NF-kB, stimulate tumor-associated CAFs and PSCs to produce specific fibrogenic cytokine mediators such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF-β) that lead to the growth of tumor cells and fibrosis formation [2], [31], [32]. Furthermore, TGF-β contributes to forming a dense stroma by promoting the formation of collagen, an extracellular matrix (ECM) component that masks the tumor cells and evades immune system [33], [34], [35]. At PDAC normal tissue margins, cytokines CCL2, CXCL1 (C-X-C motif chemokine ligand 1), CXCL5 (C-X-C motif chemokine 5), and CXCL8 (C-X-C motif chemokine ligand 8) from tumor cells, CAFs, and macrophages recruit various immune cells, including monocytes, macrophages, neutrophils, and MDSCs (Myeloid-derived suppressor cells), respectively, which further strengthen TME immunosuppression [36], [37], [38]. Another crucial chemokine, CXCL12 (C-X-C motif chemokine 12) from CAFs, can bind to CXCR4 (C-X-C chemokine receptor 4) receptors on tumor cells driving their proliferation, migration, and chemotherapy resistance [39], [40]. This continuous complex process of cytokine signaling intercommunication between tumor, stroma, and immune compartments reprograms the PDAC microenvironment and helps to shift the immune responses towards tumor progression and establishment. Furthermore, tumor-promoting pro-inflammatory cytokines IL-10 (Interleukin 10) and TGF-β secreted from immune cells, Tregs and macrophages, orient monocytes into the M2 tumor-associated macrophages (TAMs) and assist more IL-10 and CCL18 (C-C motif chemokine ligand 18) secretion to promote a tumor supportive immunosuppressive milieu via enhancing pro-inflammatory signals and by depleting anti-tumor cytotoxic T lymphocytes (CTLs) [41], [42], [43]. Although specific chemokines like CCL5 (Chemokine (C-C motif) ligand 5) and CXCL10 (C-X-C motif chemokine ligand 10) attract anti-tumor immune cells towards TME, enriched pro-inflammatory cytokine levels favor an immunosuppressive environment and influence tumor cell stemness and metastasis [38], [44], [45], [46]. This combined complex cytokine network of pro-inflammatory and fibrosis from stromal and immune cells establishes a fibro-inflammatory TME and promotes immune evasion and PDAC tumor progression.

Various key cytokine signaling proteins secreted by cancer cells, immune cells, stromal fibroblasts, and macrophages coordinate the function and interaction of immune and non-immune cells (such as CAFs, endothelial cells) in PDAC-TME through regulation of proliferation, differentiation, migration, and cell death [47], [48]. This creates immunosuppressive and tumor-supportive environments. Cytokines such as CCL-3 and CXCL-8 recruit and activate immune cells at the tumor site, while TGF-β and INF-α polarize and differentiate macrophages into pro-tumor (M2) and anti-tumor (M1) phenotypes [49]. The pro-inflammatory cytokines secreted by tumor-infiltrating TAMs influence Tregs and Th17 cell recruitment and suppress cytotoxic T cell activity, thereby inhibiting immune and anti-tumor response evasion [50]. Simultaneously, cytokines stimulate non-immune stromal cells–CAFs to activate, proliferate, and form a dense extracellular matrix-fibroinflammatory stroma that supports tumor progression [13]. Additionally, cytokine-VEGF promotes endothelial cell angiogenesis, aiding nutrient and oxygen supply to the tumor [51]. TGF-β, IL-6, IL-1β, TNF-α, and IL-22 induce epithelial to mesenchymal transition, supporting tumor invasion and metastasis [52]. Dysregulated IL-8 and IL-6 pathways enable tumor cells to enhance cancer stem cell traits and resistance to therapy [53]. INF-α acts directly on cancer cells to induce apoptosis and cell cycle arrest, while contributing to immunosuppression by promoting the secretion of programmed death-ligand, indoleamine 2,3-dioxygenase, and IL-10 [54]. It promotes anti-tumor immune responses by activating cytotoxic CD8 + T cells, natural killer cells, and influencing myeloid cell polarization toward an anti-tumor N1-like phenotype. IL-2 supports dendritic cell expansion and activates T and NK cells for anti-tumor responses whereas high levels can promote immunosuppression and transform PDAC-TME from cold to hot tumors [37]. IL-6 promotes pro-tumor effects through intrinsic signaling pathways within tumor cells and enhances stromal cell growth and angiogenesis. It also creates an immunosuppressive environment by inhibiting T cell responses, recruiting MDSCs and macrophages, boosting Tregs function, and reprogramming host metabolism [55]. IL-8/CXCL8 attracts immunosuppressive MDSCs and neutrophils to the tumor, promotes neutrophil extracellular trap (NET) formation, influences neutrophil-dendritic cell interactions, and favors tumor growth and immunosuppression. Additionally, IL-8 stimulates angiogenesis by promoting endothelial cell proliferation, survival, and restructuring, further enhancing tumor and stromal cell interactions through its own expression [56]. PDAC tumor cells evade immune recognition by secreting immune-inhibitory cytokine IL-10, which recruits and stimulates cytotoxic CD8+ T cells and NK cells facilitating immunosuppression [57]. TGF-β plays a critical and complex role in microenvironment by promoting tumor growth through suppression of anti-tumor immune cells like cytotoxic T lymphocytes and dendritic cells, stimulating Tregs differentiation and expansion, and MDSCs accumulation to facilitate immune evasion [58]. It also contributes to fibrosis by transforming non-immune fibroblasts into CAFs, promoting EMT transition, and metabolic changes such as glycolysis. In PDAC, GM-CSF fosters inflammatory crosstalk, drives early accumulation of MDSCs and pro-tumor N2 neutrophils, and polarizes macrophages into M2 phenotypes. It exhibits anti-tumor effects by activating macrophages and differentiating dendritic cells but is often exploited by tumor cells to create an immunosuppressive environment [59]. TNF-α promotes tumor progression by facilitating immunosuppression through activation of regulatory T cells and expression of immune checkpoint inhibitors like PD-L1. It also activates macrophages and NK cells, impacting tumor cell proliferation, tumorigenesis, and stromal remodeling (desmoplasia) [60]. CCL18 and CCL19 chemokines orchestrate immunosuppression by recruiting and polarizing Tregs and macrophages and mediates tumor aggressiveness via angiogenesis and invasion. CXCL12, binding to CXCR4 and CXCR7 receptors on tumor and stromal cells, exerts pro-tumorigenic effects by attracting MDSCs and Tregs, suppressing anti-tumor responses, and supporting angiogenesis, cancer stemness, and metastasis [61]. Elevated CXCL12 facilitate immune evasion by upregulating PD-L1 expression, promoting CD8+ T cells, natural cells, and dendritic cells infiltration. CXCL5 enhances tumor invasiveness by attracting neutrophils and myeloid cells and modulates the tumor microenvironment and immunosuppressive responses [62]. IL-1β interacts with tumor cells and fibroblasts and fosters desmoplasia and angiogenesis via recruiting and activating TAMs, MDSCs, and neutrophils immune cells supporting pro-tumor inflammation and immune evasion. VEGF promotes immunosuppression by suppressing T cell, Treg, and MDSC function and impairing dendritic cell activity, and promotes tumor growth via angiogenesis and vascular permeability [63]. Overall, the intricate interactions among immune and non-immune tumor and stromal cells in the TME orchestrate PDAC progression and resistance to therapy.