Neuroinflammation constitutes an immune response to central nervous system (CNS) injury, characterized principally by microglial and astrocytic activation alongside infiltration of peripheral immune cells (11). Within depression models, sustained microglial activation accompanied by elevated pro-inflammatory mediators is characteristically observed. Microglial priming is critically orchestrated through Toll-like receptors (TLRs; notably TLR4): TLR4 binding to its agonist initiates myeloid differentiation primary response 88 (MyD88)-dependent signaling, inducing interleukin-1 receptor-associated kinase (IRAK) autophosphorylation. Following dissociation of phosphorylated IRAK from MyD88, phospho-IRAK interacts with TNF Receptor-Associated Factor 6 (TRAF6), thereby activating the Transforming Growth Factor Beta-Activated Kinase 1 (TAK1) complex. This complex subsequently propagates two principal inflammatory signaling cascades: the Mitogen-Activated Protein Kinase (MAPK) pathway and the nuclear factor-κB (NF-κB) pathway. These cascades collectively drive:expression of pro-inflammatory genes (including tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL - 6], and pro-interleukin-1β [pro-IL-1β, the precursor to interleukin-1β]) and activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome (12).

Concomitantly, peripheral inflammatory mediators—such as IL - 1β, IL - 6, TNF-α, interferon-gamma (IFN-γ), and chemokine (C-C motif) ligand 2 (CCL2)—compromise blood-brain barrier (BBB) integrity, increasing its permeability. This facilitates parenchymal infiltration of both these mediators and peripheral immune cells. Such infiltration not only directly potentiates CNS inflammation but also further stimulates microglial activation. Activated microglia, in turn, secrete copious cytokines and chemokines, propagating a self-reinforcing inflammatory cycle that perpetuates and intensifies the neuropathological process (13).

Peripheral inflammation is the body’s protective immune response to extra-central nervous system injury and involves the release of pro-inflammatory cytokines (14). In patients with MDD, chronic stress induces persistent activation of the HPA axis, resulting in sustained hypercortisolemia. Elevated cortisol levels impair glucocorticoid receptor (GR) functionality within immune cells, attenuating their inhibitory regulation of NF-κB and thereby facilitating continuous release of pro-inflammatory mediators (15).

Concurrently, significant immune cell dysregulation is observed: circulating pro-inflammatory Ly6C⁺ monocytes and neutrophils are elevated, secreting IL - 6, TNF-α, and matrix metalloproteinase 8 (MMP8), which collectively compromise vascular endothelial integrity and increase BBB permeability (16). Furthermore, an expansion of T helper 17 (Th17) cells—characterized by interleukin-17 (IL - 17) secretion—alongside a reduction in regulatory T cells (Tregs), culminates in loss of immunosuppressive capacity, thereby instigating a persistent systemic inflammatory state (17).

Additionally, mitochondrial dysfunction induces excessive generation of reactive oxygen species (ROS), causing oxidative damage to mitochondrial DNA (mtDNA). The subsequent release of damaged mtDNA into systemic circulation upregulates IL - 6 and TNF-α expression via activation of the Toll-like receptor 9 (TLR9)/NF-κB pathway (17). Gut microbiota dysbiosis, exemplified by increased Enterococcus spp. abundance, disrupts intestinal barrier function and facilitates translocation of lipopolysaccharide (LPS) into the bloodstream, thereby activating the TLR4/NF-κB signaling cascade (13).

Collectively, these interconnected mechanisms drive the sustained systemic inflammatory state characteristic of MDD patients.

IL-6 is a pleiotropic pro-inflammatory cytokine whose biological functions depend on the formation of a complex comprising IL - 6, either membrane-bound or soluble IL - 6 receptor (mIL-6R/sIL-6R), and the signal-transducing subunit glycoprotein 130 (gp130), through which it activates downstream signaling pathways to exert its biochemical effects (30). In the context of depression, significant alterations in both central and peripheral IL - 6 levels have been observed. Consistent clinical evidence indicates elevated IL - 6 concentrations in the peripheral blood, serum, plasma, and cerebrospinal fluid of individuals with MDD, with these levels positively correlating with depression severity and disease progression{sp} (25, 31 – 33){/sp}.Furthermore, treatment with selective serotonin reuptake inhibitors (SSRIs) has been associated with a reduction in circulating IL - 6 levels in some patients (34), suggesting that antidepressant therapy may partially reverse this inflammatory state.

These findings establish a clear link between IL - 6 and depressive pathology; however, existing evidence remains limited. Most conclusions are derived from cross-sectional studies, and there is a scarcity of large-scale longitudinal cohort data to substantiate a causal relationship between IL - 6 dynamics and the course of depression. Although SSRIs may reduce IL - 6 in certain cases, the antidepressant efficacy of directly targeting the IL - 6 receptor—such as with tocilizumab—has not been conclusively demonstrated in human studies, despite promising results in animal models and limited clinical translation (35).

Depression is associated with expanded monocyte and neutrophil populations. MDD directly activates monocytes and macrophages, enhancing IL - 6 production (36). Depressive states also trigger HPA axis activation, increasing glucocorticoid secretion. While glucocorticoids typically exert protective effects through GR binding, chronic HPA overactivity causes sustained glucocorticoid elevation, inducing GR resistance and impairing GR function in immune cells. This disrupts IL - 6 suppression, further elevating IL - 6 levels (7).

The gut microbiota in depressed patients also shows distinct dysbiosis relative to healthy individuals, marked by reduced diversity, compositional changes, expansion of pro-inflammatory bacteria, and loss of anti-inflammatory taxa. These shifts induce expression of mucosal inflammatory markers like TLR4, damage the gut barrier, and raise permeability, enabling endotoxins such as LPS to enter the bloodstream. This triggers immune activation and inflammatory cytokine release, including IL - 6 (37, 38).

In summary, elevated IL - 6 and its mechanistic links to depression reinforce the inflammatory hypothesis of the disorder and suggest anti-inflammatory therapy as a promising direction. However, clinical translation remains limited: current evidence relies largely on cross-sectional data, impeding causal conclusions about IL - 6 in depression. Although SSRIs may lower IL - 6 in some patients, direct IL - 6 pathway inhibition—such as with tocilizumab—has not demonstrated robust antidepressant efficacy in human studies, highlighting persistent translational barriers. Large longitudinal studies are urgently needed to establish causality and advance personalized anti-inflammatory treatment strategies, including predictive biomarkers of response.

The IL - 6–IL-6R–gp130 complex activates Janus Kinases (JAKs), thereby initiating multiple downstream signaling cascades. The first is the JAK–STAT3 pathway, wherein JAK induces autophosphorylation, facilitating dimerization and nuclear translocation of the signal transducer and activator of STAT3, ultimately mediating intracellular signal transduction and regulating gene expression (39).The second involves the MAPK/Extracellular Signal-Regulated Kinase (ERK) pathway: JAK activates the RAS–RAF cascade, resulting in hyperphosphorylation of MAPK and promoting cellular proliferation (40).The third entails the Phosphoinositide 3-Kinase–Protein Kinase B (PI3K–AKT) pathway, through which JAK phosphorylates and activates PI3K, converting phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol (3–5)-trisphosphate (PIP3). PIP3 in turn phosphorylates and activates AKT, a regulator of cell survival (41).

Chronic inflammation associated with depression may elevate IL - 6 levels, thereby modulating the expression of various genes involved in cellular proliferation, differentiation, and metastasis. These processes contribute to the formation of a tumor-promoting microenvironment and enhance the survival and proliferative capacity of cancer cells. The precise mechanisms by which IL-6 facilitates tumor biological processes through downstream signaling are illustrated in Figure 2.

TNF-α is a pleiotropic cytokine that orchestrates a dual role in cancer progression by modulating both apoptotic and proliferative pathways (54). Consistent clinical evidence indicates that patients with MDD exhibit significantly elevated serum concentrations of TNF-α compared to healthy controls, with levels positively correlating with HAMD scores (55, 56). Treatment with SSRIs has been shown to substantially reduce TNF-α levels, suggesting a partial amelioration of the inflammatory state (34).

In preclinical studies, anti-TNF-α monoclonal antibodies (e.g., infliximab) demonstrate rapid antidepressant effects in murine models, including behavioral improvements, suppression of hippocampal astrocyte activation, and reduced neuronal apoptosis (57). However, corresponding clinical trials in humans have not unequivocally supported their efficacy as monotherapy for depression. This discrepancy may be attributed to limited blood-brain barrier penetration of monoclonal antibodies and the more complex neuroimmune-neurotransmitter interactions inherent to human neurobiology (58).

Hyperactivity of the HPA axis in MDD leads to elevated cortisol levels and subsequent GR resistance, which impairs the negative regulation of TNF-α release and contributes to its increased systemic concentrations (7). Depressive states are frequently accompanied by gut microbiota dysbiosis and upregulation of inflammatory mediators within the intestinal mucosa, resulting in compromised barrier integrity and enhanced permeability. This dysfunction facilitates translocation of LPS into systemic circulation, where it activates peripheral immune cells and stimulates TNF-α secretion (37, 38).Animal studies further demonstrate that LPS administration induces elevated serum TNF-α levels and depression-like behaviors in mice. Pretreatment with SSRIs, such as fluoxetine or paroxetine, effectively attenuates these responses (59).

Elevated TNF-α represents a prominent inflammatory biomarker in major depression, correlating with disease severity and demonstrating partial reversibility following SSRI treatment. Although TNF-α inhibition (e.g., with infliximab) has shown efficacy in animal models, its utility as monotherapy for human depression remains limited. This discrepancy underscores the complexity of translating fundamental inflammatory mechanisms into effective clinical interventions. Key challenges include restricted blood-brain barrier permeability of biologic agents, divergence between human neuroimmune circuitry and animal models, and the multifactorial etiology of depression—encompassing HPA axis dysregulation, gut microbiota disruption, and subsequent LPS translocation.

Future therapeutic strategies must extend beyond singular targets toward integrated, multidimensional approaches that concurrently modulate the HPA–immune–gut–brain axis. Moreover, the potential of anti-inflammatory augmentation therapy warrants rigorous evaluation, particularly in defined inflammatory subtypes of depressed patients.

TNF-α functions as a transmembrane homotrimeric protein that undergoes proteolytic processing by convertase enzymes, yielding two principal isoforms: membrane-bound (mTNF-α) and soluble (sTNF-α). Its physiological effects are mediated through engagement with distinct receptors, with functional outcomes contingent upon receptor specificity. Binding to tumor necrosis factor receptor 1(TNFR1) enables TNF-α to activate pro-inflammatory gene expression and promote cancer progression via pathways such as NF-κB, while also triggering programmed cell death through both apoptosis and necroptosis (54, 60). In contrast, tumor necrosis factor receptor 2(TNFR2) is primarily associated with cellular proliferation and survival (61). Thus, TNF-α orchestrates pivotal roles in inflammatory responses, immune regulation, and tumorigenesis. The dual role of TNF-α in promoting apoptosis and cell growth, and its regulation of key oncogenic pathways, is illustrated in Figure 3.

IL-1β is a central cytokine in innate immunity and inflammatory responses, as well as a key mediator in various pulmonary inflammatory diseases. Its biological activity depends on the formation of a trimeric signaling complex with Type I Interleukin-1 Receptor (IL - 1RI) and the Interleukin-1 Receptor Accessory Protein (IL - 1RAcP), which initiates downstream signaling cascades and drives inflammatory processes (76, 77).

In MDD, findings regarding IL - 1β levels are inconsistent across studies: multiple reports indicate significantly elevated concentrations of IL - 1β in the peripheral blood or serum of patients, positively correlating with depression severity (31, 78). Animal models further demonstrate that LPS-induced activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is accompanied by increased IL - 1β (79). However, some meta-analyses show no significant difference in IL - 1β levels between MDD patients and healthy controls (80). These discrepancies may stem from sample heterogeneity (55), methodological variations, or the unique secretory dynamics of IL - 1β—which is released via non-canonical pathways such as exosomal delivery or Gasdermin D pore formation, and is tightly regulated by the extracellular microenvironment. These factors complicate accurate in vitro quantification of its in vivo bioactivity (81).

Moreover, the pathological effects of IL - 1β are modulated by other biomarkers; for instance, levels of Brain-Derived Neurotrophic Factor (BDNF) significantly influence its impact. When soluble BDNF is low, each 1 pg/mL increase in IL - 1β elevates the risk of antidepressant treatment failure by 17%. In contrast, high BDNF levels completely mitigate this detrimental effect, underscoring the context-dependent contribution of IL - 1β to immunopathology (82).

Depression, as a state of chronic psychological stress, activates the NLRP3 inflammasome through multiple mechanisms. Upon assembly, the inflammasome facilitates the autocleavage of pro-caspase-1 into enzymatically active caspase-1, which in turn cleaves the immature pro-IL-1β into its mature form and promotes its extracellular secretion (83). Furthermore, depression contributes to elevated IL - 1β levels through sustained hyperactivity of the HPA axis (7), aberrant activation of peripheral monocytes and macrophages (36), and disruption of gut microbiota composition (37, 38).

Although several studies support a positive correlation between peripheral IL - 1β levels and both depression severity and lung cancer progression, its clinical utility remains constrained by methodological limitations—such as insufficient sensitivity of current assays to capture non-canonical secretion pathways and bioactive forms of IL - 1β—as well as population heterogeneity, with more pronounced alterations often observed in treatment-resistant depressive subtypes. The biological effects of IL - 1β are highly context-dependent; for instance, higher levels of BDNF can completely counteract its pathological impact, indicating that a single inflammatory marker is insufficient for reliable clinical interpretation.

Future research should focus on developing multidimensional assessment frameworks that integrate inflammatory subtypes, neurotrophic factors, and metabolic parameters. Additionally, targeted investigation into dual-intervention strategies aimed at the IL - 1β signaling pathway in patients with comorbid depression and lung cancer is warranted to transcend the current impasse of “mechanistic clarity amid translational challenges.”

Depressive states can elevate peripheral blood levels of IL - 1β, a cytokine that plays a critical role in the initiation and progression of malignant tumors. IL - 1β exerts its effects by forming a complex with the IL - 1R1 and its accessory protein IL - 1RAcP. This complex activates both p38 and JNK signaling pathways, leading to the activation of the transcription factor AP1. Concurrently, it stimulates the IKK complex, resulting in the phosphorylation and degradation of Inhibitor of IκB-α, which releases NF-κB and facilitates its nuclear translocation, thereby initiating the transcription of NF-κB-dependent genes (84).

Furthermore, IL - 1β serves as a pivotal driver in the development and metastasis of mesenchymal and epithelial-derived tumors. It induces the acetylation of the mitochondrial inner membrane protein Nicotinamide Nucleotide Transhydrogenase (NNT), enhancing its catalytic activity. This promotes the synthesis of Nicotinamide Adenine Dinucleotide Phosphate (NADPH), maintains iron-sulfur cluster homeostasis, and consequently inhibits ferroptosis in tumor cells (85). IL - 1β also activates the PI3K–AKT signaling pathway, inducing epithelial–mesenchymal transition (EMT) in non-small cell lung cancer (86), and synergistically promotes tumor growth and metastatic processes by stimulating the production of various growth factors, including VEGF (77).

Finally, IL - 1β upregulates glycolytic activity in lung adenocarcinoma cells via the p38MAPK pathway, further enhancing their migratory, invasive, and metastatic capabilities (87). The mechanisms by which IL-1β promotes tumor growth and metastasis through downstream signaling cascades are illustrated in Figure 4.

Although IL - 1β represents a pivotal theoretical nexus linking depression and cancer, its clinical translation faces dual challenges: while mechanistic studies have confirmed that IL - 1β promotes lung cancer progression through activation of the NF-κB/AP-1 signaling pathways, induction of EMT, and metabolic reprogramming—such as inhibition of ferroptosis and enhancement of glycolysis—its elevation in depressive states exhibits pronounced heterogeneity. This variability is constrained by methodological limitations in detection, such as the failure to account for non-canonical secretion pathways and bioactive forms, as well as complex biomarker interactions—for instance, the modulatory countereffect of BDNF—which collectively undermine its reliability as a therapeutic target in comorbid conditions. There is an urgent need for prospective cohort studies in patients with depression and lung cancer to validate the dual efficacy of targeting the IL - 1β pathway (e.g., assessing whether anti-inflammatory interventions simultaneously improve psychological and oncological outcomes).

Furthermore, the development of a dynamic monitoring framework incorporating microenvironment-specific biomarkers is essential to bridge the gap between “well-established mechanisms and insufficient c IL - 1βIL-6, TNF-α, and IL - 1β serve as key inflammatory mediators in depression, each promoting tumor proliferation, metastasis, and metabolic reprogramming through activation of shared signaling pathways such as NF-κB, MAPK, and PI3K/AKT. However, their clinical relevance exhibits notable divergence: although elevated levels of IL - 6 and TNF-α show relative consistency across depression and cancer contexts—correlating with disease stage and treatment response (e.g., reduction following SSRI therapy)—the evidence regarding IL - 1β remains markedly contradictory. While some studies report positive correlations between IL - 1β levels and both depression severity and cancer progression, several meta-analyses have found no significant difference between patients with depression and healthy controls. These discrepancies may stem from methodological limitations in detecting non-canonical secretory pathways (e.g., exosome-mediated transport), context-dependent regulatory effects (such as counteracting interactions with BDNF), and heterogeneity across depressive subtypes.

Such inconsistencies underscore the limitations of relying on any single cytokine as a trans-diagnostic biomarker or therapeutic target. Future research should aim to integrate multidimensional markers—including inflammatory subtypes, neurotrophic factors, and metabolic profiles—and conduct well-designed prospective cohort studies to validate the dual therapeutic potential of targeting these pathways in patients with comorbid depression and cancer. A summary of the mechanism and clinical significance of IL-6, TNF-α, and IL-1β in cancer progression is provided in Table 2.