Effect of SASPs on Cancer Progression

Effect of IL-6 on Cancer Progression

Interleukin-6 (IL-6) signaling exerts a net pro-tumorigenic effect on many cancers, where this pleiotropic cytokine contributes to disease pathogenesis by facilitating tumor development, progression, and aggressive clinical behavior [89]. IL-6 exerts its effects primarily via the JAK/STAT3 axis. Following receptor engagement, JAK-mediated phosphorylation activates STAT3, allowing it to translocate to the nucleus and transcribe a pro-tumorigenic program encompassing cell cycle progression, apoptotic resistance, invasion, and blood vessel formation which is a key process in hepatocarcinogenesis [90, 91]. High levels of IL-6 in the TME, largely derived from TAMs, contribute to immunosuppression while simultaneously activating a pro-tumorigenic feedback loop via the STAT3 pathway. This signaling axis drives malignant progression by increasing cancer stem cell properties and invasive capacity [92]. The clinical significance of this pathway is underscored by the association between high circulating IL-6 levels and adverse outcomes, including early recurrence, treatment resistance, and poor survival, positioning IL-6/STAT3 signaling as a promising target for novel therapies [93].

The pro-tumorigenic role of IL-6 via JAK/STAT3 is one of the best-supported mechanisms in cancer biology, with consistent evidence across multiple cancer types, in vitro systems, and animal models. Importantly, elevated circulating IL-6 has been associated with poor prognosis in human clinical studies across breast [94], colorectal [95–97], and hematological malignancies [98–100], lending this axis a degree of translational validity that not all SASP factors yet possess. A notable area of controversy, however, is the finding that IL-6 also plays roles in anti-tumor immune activation particularly in the early stages of tumor surveillance meaning that systemic IL-6 blockade carries the theoretical risk of impairing protective immunity [101, 102]. This dual role suggests that therapeutic targeting of IL-6 signaling will require careful patient stratification and context-specific dosing strategies.

Effect of IL-8 on Cancer Progression

In cancer, elevated levels of the chemokine IL-8 (CXCL8), a key driver of tumor invasion and metastasis, are strongly associated with aggressive clinicopathological features, such as advanced tumor stage, vascular invasion, and early recurrence, culminating in poor patient survival [103–105]. The role of IL-8 extends to shaping an immunosuppressive TME, and its elevated levels are associated with innate resistance to immune-based and systemic therapies. This dual function provides a compelling rationale for developing IL-8/CXCR1/2 axis inhibitors to reverse immunosuppression and improve therapeutic outcomes in cancer [106–110].

The prognostic and mechanistic evidence for IL-8 in cancer is growing but is currently less uniformly established across cancer types than the IL-6/STAT3 axis. Much of the mechanistic data for IL-8-driven invasion, angiogenesis, and immunosuppression derives from in vitro cell line experiments or xenograft models; large-scale human clinical data validating IL-8 as an independent driver, rather than a correlate, of aggressive biology in obesity-associated cancers specifically are sparse. IL-8/CXCR1/2 inhibitors remain in early-phase clinical development, and their therapeutic utility in the obesity-cancer context is currently speculative rather than evidence-based.

Effect of MCP-1 on Cancer Progression

Monocyte chemoattractant protein-1 (MCP-1/CCL2) exerts a profound pro-tumorigenic effect in HCC, primarily by orchestrating an immunosuppressive TME. MCP-1 is upregulated in both HCC tissue and patient serum, where it functions to recruit CCR2-expressing monocytes and macrophages into the liver, a critical step in tumor progression [111]. Upon infiltration, these CCR2 + monocytes differentiate into TAMs, predominantly adopting an M2-polarized, pro-tumorigenic phenotype [112–114]. These M2 TAMs facilitate cancer progression by secreting a repertoire of growth factors and immunosuppressive cytokines that create a permissive tumor niche [115, 116]. Independent of its role in recruitment, the CCL2/CCR2 axis directly enhances HCC malignancy by activating oncogenic pathways such as Hedgehog (Hh) and TGF-β. This direct signaling promotes key aggressive traits, including cancer cell migration, invasion, angiogenesis, epithelial-mesenchymal transition (EMT), and ultimately, metastatic dissemination and post-surgical recurrence [117]. During obesity, adipocytes in both human and murine breast tissues recruit and stimulate macrophages via a previously unidentified CCL2/IL-1β/CXCL12 signaling pathway [118]. Postmenopausal obesity may enhance CCL2 production in breast adipose tissue, thereby intensifying menopause-associated inflammation and further promoting local aromatase activity and estrogen production, which collectively increase breast cancer risk [119]. In colorectal cancer, adipocytes from obese and CRC subjects were found to release higher amounts of pro-inflammatory and immunoregulatory cytokines/chemokines (IL-6, CXCL8, CCL2, IL-10) with respect to lean healthy subjects [120]. In ovarian cancer model, MCP‑1 secreted by omental adipocytes binds to its receptor CCR2 on ovarian cancer cells, promoting cell migration and omental metastasis through activation of the PI3K/AKT/mTOR pathway and downstream mediators HIF‑1α and VEGF‑A in cell lines, xenograft, and transgenic mouse models. In vivo, neutralization of MCP‑1 significantly reduced tumor burden and improved survival. Overall, the MCP‑1/CCR2 axis between adipocytes and cancer cells plays a key role in facilitating peritoneal metastasis in ovarian cancer [121].

Given that elevated MCP-1 is an independent predictor of poor survival and treatment failure after TACE, targeting the CCL2/CCR2 axis represents a rational and compelling therapeutic strategy for improving outcomes in HCC [122]. While MCP-1’s role as a macrophage recruiter is a broadly conserved biological function, the specific downstream consequences of CCL2/CCR2 axis activation, including TAM polarization states and their pro-tumorigenic outputs — are known to be cancer-type and microenvironment-specific. The degree to which MCP-1-driven immunosuppression in HCC generalized to other obesity-associated cancers such as endometrial, renal, or breast cancer has not been systematically studied, and extrapolation should be made with caution. Furthermore, clinical trials targeting CCL2/CCR2 have yielded modest results in several tumor types, suggesting that MCP-1 is a necessary but not sufficient driver of the immunosuppressive TME.

Effect of IL-1β on Cancer Progression

Interleukin-1β (IL-1β) is a master pro-inflammatory cytokine that serves as a critical mechanistic link between chronic inflammation and cancer, playing a complex but net pro-tumorigenic role in tumor development and progression [123]. Elevated serum levels of IL-1β, particularly in patients with chronic hepatitis, are significantly associated with an increased risk of cancer development and poorer prognosis [124, 125]. Within TME, IL-1β is predominantly secreted by activated immune cells, notably TAMs, and mediates its effects by signaling through the IL-1R1 receptor on both malignant and stromal cells [126]. IL-1β fosters cancer progression by directly promoting tumor cell invasion [127], stimulating angiogenesis [128], and subverting anti-tumor immunity through PD-L1 induction and MDSC accumulation [129, 130]. Moreover, a key pathogenic feature is the synergistic loop between IL-1β/NF-κB signaling and hypoxia (HIF-1α), which perpetuates a chronic inflammatory state that drives the most aggressive aspects of HCC [131]. Effects of SASPs are illustrated in Fig. 1.

Among the four SASP factors reviewed in this section, IL-1β has the strongest translational evidence for a causal role in human oncogenesis. The CANTOS trial, a large randomized controlled trial of IL-1β blockade with canakinumab, demonstrated a significant and dose-dependent reduction in lung cancer incidence and cancer-related mortality in a metabolically inflamed human population, providing clinical proof-of-concept for the IL-1β-cancer mechanistic axis (NCT01327846). This distinguishes IL-1β from IL-8 and MCP-1, where the evidence remains predominantly preclinical. However, the IL-1β/cancer relationship is not straightforward: IL-1β also contributes to anti-tumor immune activation in certain contexts, and broad systemic blockade in CANTOS was associated with increased fatal infection risk, highlighting the therapeutic complexity of targeting a cytokine with both pro- and anti-tumorigenic roles depending on the immunological context.

Fig. 1: Effects of SASPs secretion on Cancer. Schematic illustration depicting the effects of SAPs on tumor progression and the tumor microenvironment (TME). Adipocyte-derived factors, including IL‑6 and MCP‑1, promote tumor cell proliferation and contribute to enhanced angiogenesis, with additional involvement of IL‑1β and IL‑8. IL‑6 signaling also inhibits apoptosis in tumor cells. Collectively, these cytokine-mediated interactions drive remodeling of the TME, favoring tumor growth and vascularization. Solid arrows indicate stimulation, red lines indicate inhibition, and dashed arrows represent broader changes in the TME. IL-6: Interleukin 6, IL-8: Interleukin 8, IL-1β: Interleukin-1 beta, MCP-1: Monocyte Chemoattractant Protein-1, SASPs: Senescence associated secretory phenotype