Review Article

Mechanistic Links Between Depression and Lung Cancer Progression: Therapeutic Implications of Antidepressants

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DOI:

10.3791/69574

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February 20th, 2026

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1Department of Thoracic Oncology, Shulan (Hangzhou) Hospital, Shulan International Medical College, Zhejiang Shuren University

In This Article

Summary

This narrative review explores the biological mechanisms linking depression to lung cancer progression, focusing on neuroendocrine and immune pathways. It also examines evidence for the antitumor potential of various antidepressant classes. Understanding these interactions may inform integrated treatment strategies to improve outcomes for lung cancer patients with comorbid depression.

Abstract

Lung cancer remains a leading cause of cancer-related mortality worldwide. Depression, highly prevalent in lung cancer patients, not only impairs quality of life but also adversely affects disease progression and treatment outcomes through complex biological pathways. Previously considered merely a psychological reaction, depression is now recognized as sharing bidirectional pathophysiological interactions with lung cancer. This narrative review comprehensively reviews current evidence on the molecular mechanisms linking depression to lung cancer progression, with a focus on dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), cytokine-mediated inflammation, and the lung-brain axis involving BDNF/TrkB signaling. We also discuss the potential therapeutic implications of antidepressants, including their effects on apoptosis, autophagy, and immune modulation. Key findings suggest that depression promotes tumor progression via chronic stress pathways, while antidepressants may counter these effects through multiple mechanisms. Understanding these pathways may inform integrated treatment strategies and improve prognosis in lung cancer with comorbid depression.

Introduction

Lung cancer is the most common malignant tumor globally. According to the latest statistics from the International Agency for Research on Cancer (IARC), there were 2.5 million new cases and 1.8 million deaths from lung cancer worldwide in 2022, accounting for 12.4% and 18.7% of the total number of new cases and deaths from malignant tumors globally, respectively1. Lung cancer can be classified into two subtypes: Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC). Among these, Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 80% of lung cancer cases, with the majority of patients being diagnosed at an advanced, inoperable stage2. Therefore, systemic chemotherapy is the primary treatment method to improve patient survival and quality of life3. Despite significant breakthroughs in targeted therapy and immunotherapy in recent years that have notably enhanced the survival period for some patients, the overall prognosis remains unfavorable, with treatment resistance and disease recurrence posing significant challenges in clinical practice4.

Depression is a chronic mood disorder characterized by a series of unique phenomenological features, including feelings of sadness, loss of interest or pleasure, sleep and appetite disturbances, and is a common form of psychological distress among cancer patients5. Recent research findings indicate a higher risk of depression following a cancer diagnosis compared to other illnesses, leading to an increased mortality rate among cancer patients6,7. Epidemiological surveys have shown that depression is most prevalent in lung cancer among all cancer subtypes. The average prevalence of depression in cancer patients is around 15%, with a significantly high proportion of clinically significant depression and/or anxiety symptoms in lung cancer patients, ranging from 21% to 44%, much higher than in other cancer populations, which range from 7% to 23%8. While depression comorbidity exists across multiple cancers, lung cancer shows the highest prevalence and distinct mechanistic patterns, particularly involving HPA-immune coupling. Previous reviews have not provided an integrated framework linking neuroendocrine dysregulation and antidepressant antitumor action. Yet, the molecular mechanisms linking depression and lung cancer progression remain fragmented and poorly synthesized.

This narrative review synthesizes current evidence on how depression-related neuroendocrine and immune alterations influence lung cancer progression and examines the mechanistic and therapeutic implications of antidepressant use. We focus primarily on preclinical and clinical evidence related to NSCLC and explore three key biological systems: the HPA/SNS axis, inflammatory signaling, and the lung-brain axis, which form an interdependent network mediating tumor progression. Given that many antidepressants modulate these same signaling pathways, their potential dual role in mood and tumor regulation warrants closer examination. Understanding these bidirectional biological links may guide integrative therapeutic approaches to improve outcomes for patients with lung cancer and comorbid depression.

Review and Perspective

This narrative review was based on a comprehensive literature search in PubMed, Web of Science, and Google Scholar from inception to 2025, using keywords including 'depression', 'lung cancer', 'antidepressants', 'HPA axis', 'sympathetic nervous system', 'inflammation', 'BDNF', 'SSRIs', 'SNRIs'. We included both preclinical and clinical studies exploring mechanisms and therapeutic effects.

1. Clinical association between depression and lung cancer prognosis

An increasing body of evidence suggests that depression and anxiety in cancer patients are associated with higher medical costs9 and lower adherence to cancer treatment10,11. A retrospective data analysis of 5,055 cancer patients in the United States revealed that depressed patients had significantly higher annual medical visits, emergency department visits, and hospitalizations compared to non-depressed cancer patients12. Furthermore, depression and anxiety may significantly impact patient comfort, quality of life, and the ability to make appropriate treatment decisions, thereby exerting a negative influence on survival13,14. Chen et al.15 found that non-small cell lung cancer patients with depression had an increased risk of decreased health-related quality of life (HR-QOL) and survival during chemotherapy compared to those without depression (P < 0.01). Several prospective studies focusing on lung cancer patients8,16,17 have shown a statistically significant association between higher depression scores and increased risk of lung cancer mortality.

2. Biological mechanisms of depression in promoting lung cancer progression

  1. Neuroendocrine axis dysregulation
    Chronic psychological stress is a core feature of depression, leading to the sustained activation of two major stress response systems in the body: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS)17. The HPA axis primarily mediates the secretion of glucocorticoids (GCs). In states of chronic stress induced by depression, persistently elevated levels of cortisol, a major GC, exert broad immunosuppressive effects. Preclinical studies have demonstrated that glucocorticoids can induce apoptosis of T lymphocytes and neutrophils and inhibit antigen presentation processes, thereby extensively weakening the body's adaptive antitumor immune response. A prospective study involving late-stage non-small cell lung cancer (NSCLC) patients found that individuals experiencing emotional distress (depression/anxiety) prior to treatment exhibited significantly increased peripheral blood cortisol levels, which were closely associated with poorer clinical outcomes18.
    On the other hand, the SNS primarily mediates the secretion of catecholamines such as adrenaline (E) and noradrenaline (NE)19. During periods of stress, the SNS rapidly enhances the body's alertness and resilience to cope with stress; however, under chronic stress, sustained activation of the SNS significantly elevates the expression levels of E, NE, and other neurotransmitters in the tumor microenvironment. Upon binding of NE/E to β-adrenergic receptors, this can directly promote tumor cell proliferation, migration, and invasion, and inhibit apoptosis by activating downstream signaling pathways such as PKA and MAPK20. Additionally, this signaling pathway can upregulate the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors, providing nutrients for the rapid growth of tumors21.
  2. Inflammatory response
    The occurrence and progression of tumors are characterized by continuous proliferative signaling, evasion of growth inhibitory factors, angiogenesis, resistance to cell apoptosis, and activation of invasion and metastasis. Oxidative stress can activate transcription factors and lead to the expression of over 500 different genes, including growth factors, pro-inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules. Prolonged oxidative stress can modulate chronic inflammation, potentially impacting cancer progression, suggesting a close relationship between oxidative stress, chronic inflammation, and cancer. According to the macrophage/T lymphocyte theory of depression, excessive inflammatory responses may lead to depression. Several research findings indicate that inflammation plays a role in the occurrence and development of depression. Increased expression of innate immune mediators has been observed in the peripheral blood and cerebrospinal fluid of individuals who have died by suicide, with these mediators even appearing in brain tissue22. A meta-analysis revealed elevated levels of pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α, soluble IL-2 receptor, and C-reactive protein) in the peripheral blood of major depressive disorder patients compared to the control group23. High levels of CRP in longitudinal population studies suggest a higher likelihood of subsequent depressive symptoms, supporting the view that immune system activation may be a pathological factor in depression24. Chronic stress associated with depression profoundly affects the composition and function of immune cells. Preclinical studies consistently show that chronic stress significantly reduces the proportion and cytotoxic function of effector CD8+ T cells and natural killer (NK) cells in tumor tissue.
    Simultaneously, the stress state promotes the recruitment and expansion of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)25. These cells directly inhibit the activity of effector T cells by secreting immunosuppressive cytokines (such as IL-10, TGF-β) and expressing inhibitory molecules (such as PD-L1, CTLA-4), thereby reducing the body's ability to eliminate tumor cells. Inflammatory responses also involve the upregulation of indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan to kynurenine. IDO is induced by pro-inflammatory cytokines and contributes to immunosuppression by inhibiting T cell function and promoting Treg expansion, creating an immunosuppressive tumor microenvironment. Pro-inflammatory cytokines can induce excessive activation of the HPA axis and release glucocorticoids (GC) through the phospholipase A2 (PLA2)-prostaglandin E2 (PGE2)-corticotropin-releasing factor pathway26. Inducing lymphocyte apoptosis and reducing immune function by activating glucocorticoid receptors (GR) on immune cells. GR controls the activation of the AP-1 transcription factor, which regulates the expression of genes involved in lymphocyte growth, differentiation, and transformation, reduces telomerase activity in immune cells, and accelerates immune aging27. It is well known that immune suppression or aging increases susceptibility to cancer.
  3. "Lung-Brain Axis"
    Brain-derived neurotrophic factor (BDNF) is a secretory protein belonging to the neurotrophic protein family, playing a crucial role in neural development and neuroplasticity28. BDNF promotes the growth and development of immature neurons, enhances the survival capabilities of mature neurons, and strengthens their functionality29. The lung-brain axis represents a bidirectional communication pathway between the central nervous system and the lungs. Chronic psychological stress-induced stress can trigger and exacerbate emotional disorders in cancer patients. Compared to healthy adults, cancer patients with emotional disorders exhibit reduced gray matter volume in the hippocampus and enlargement of the third ventricle30. In depression patients or in depression models induced by chronic unpredictable mild stress (CUMS), the expression of BDNF and its receptor tropomyosin receptor kinase B (TRKB) decreases31. This exerts a certain damaging effect on the survival function of neurons and increases susceptibility to neuronal damage. Chronic stress leads to reduced BDNF expression in the brain, which may influence peripheral processes through the lung-brain axis. Emerging evidence suggests that central BDNF changes can affect the peripheral tumor microenvironment, with BDNF/TrkB signaling activating pathways such as PI3K/AKT, RAS/ERK, AMPK/ACC, PLC/PKC, and JAK/STAT in tumor cells. Furthermore, crosstalk exists between BDNF signaling and inflammatory responses; BDNF may interact with pro-inflammatory cytokines like IL-6 and TNF-α to foster a pro-tumor microenvironment. It has been reported that the binding of BDNF to TrkB receptor activates signaling pathways such as PI3K/AKT, RAS/ERK, AMPK/ACC, PLC/PKC, and JAK/STAT, leading to the occurrence and malignant progression of osteosarcoma, lung cancer, and neuroblastoma32,33,34. However, the precise mechanisms by which depression/stress affects central and peripheral neurotrophic factor function in lung cancer and influences cancer development require further elucidation.

3. Targeted antitumor effects of antidepressant drugs

  1. Clinical commonly used antidepressants for cancer-depression comorbidity
    Selective serotonin reuptake inhibitors (SSRIs) are considered the first-line antidepressants for cancer-depression comorbidity due to their good tolerability, lower risk of adverse effects, and fewer drug interactions35. Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are preferred as first-line treatment options as they have shown superior efficacy and tolerability compared to SSRIs and offer potential benefits in improving neuropathic pain36. Classical tricyclic antidepressants (TCAs) are not commonly used for cancer-depression comorbidity treatment due to their lower tolerability and the possibility of treatment interruption in about one-third of patients36. Monoamine oxidase inhibitors (MAOIs) are less considered due to their numerous drug interactions with anticancer medications37. Recently, three second-generation atypical antipsychotics (SGAs) - quetiapine, aripiprazole, and olanzapine - have been approved by the FDA as adjunctive treatments for depression, commonly used in combination with antidepressants in the treatment of severe depression. They have shown good efficacy in treating severe depression and anxiety disorders38.
  2. SSRIs antidepressant drugs
    SSRIs are currently the most widely used first-line antidepressants in clinical practice, with representative drugs including fluoxetine, sertraline, and paroxetine. Their core pharmacological action involves selectively inhibiting the reuptake of 5-Hydroxytryptamine (5-HT) by the presynaptic membrane, thereby increasing the concentration of 5-HT in the synaptic cleft. SSRIs not only improve mood, but in the tumor microenvironment, T cells uptake 5-HT via the serotonin transporter (SERT), while tumor cells degrade 5-HT through enzymes like MAO-A, preventing excessive uptake of 5-HT and increasing the extracellular 5-HT signal available to T cells. Studies across various mouse and human tumor models have confirmed that SSRIs can significantly enhance the antitumor activity of T cells. When combined with programmed cell death protein 1 monoclonal antibody (PD-1 monoclonal antibody), SSRIs exhibit potent synergistic effects, even achieving complete tumor regression in some mice26.
    Among them, fluoxetine is a representative drug of SSRIs that can regulate the expression of brain-derived neurotrophic factor, tropomyosin receptor kinase B, among others, exerting neuroprotective and antidepressant effects. Yang et al.39 established a mouse depression model using CUMS in C57BL/6 mice. After subcutaneously implanting LLC lung cancer cells in depressed mice, it was found that CUMS promoted tumor growth. In vitro, fluoxetine significantly inhibited the proliferation, migration, and colony formation of A549 cells, inducing apoptosis. In vivo administration of fluoxetine not only significantly reversed the behavioral scores of depressed mouse models but also enhanced the ratio of 5-HT, tryptophan/serotonin in CUMS-bearing mice, increased the levels of immune cells CD4+ Th and CD8+ Tc cells in mice, reduced CD25+ FOXP3+ Tregs, and ultimately inhibited tumor growth. A recent large-scale retrospective cohort study by Magagnoli et al.40 provided compelling clinical evidence supporting the synergistic effects of fluoxetine with PD-1/L1 immunotherapy. The study evaluated 2316 cancer patients (including lung, throat, skin, and kidney/urinary cancers) treated with PD-1/L1 inhibitors, among whom 34 received concurrent fluoxetine treatment. Propensity score weighted Cox proportional hazards analysis demonstrated significantly better overall survival in fluoxetine-exposed patients compared to unexposed (HR: 0.59, 95% CI 0.371-0.936). The median survival time for patients receiving fluoxetine plus PD-1/L1 therapy was 523 days versus 317 days for those receiving PD-1/L1 therapy alone. Importantly, this survival benefit was specific to fluoxetine and not observed with other antidepressants such as sertraline or venlafaxine, suggesting a mechanism beyond general antidepressant effects. The authors proposed that fluoxetine's NLRP3 inflammasome inhibitory activity may underlie this synergistic effect, as NLRP3 inhibition has been shown to suppress granulocytic myeloid-derived suppressor cell (PMN-MDSC) recruitment and enhance PD-1 therapy efficacy40.
    Several studies have confirmed that SSRIs can inhibit the occurrence and development of tumors by inducing autophagy through immune-related pathways. Shao et al.41 found that paroxetine and fluoxetine significantly reduced the viability of NSCLC cell lines (H460 and A549) in a concentration-dependent manner. Further research revealed that fluoxetine concentration-dependently increased the expression levels of p62 and LC3B in A549 cells, triggering the ATF4-AKT-mTOR signaling pathway, inducing cell cycle arrest and autophagy inhibition to suppress lung cancer cell growth and proliferation. Another study demonstrated that sertraline upregulates the expression of death receptor 5 (DR5), inhibiting autophagic flux, thereby reducing lung cancer cells' resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and enhancing apoptotic sensitivity.
    Moreover, fluoxetine has been shown to inhibit the invasive and metastatic potential of lung cancer cells. An in vivo study42 revealed that fluoxetine treatment significantly decreased the expression of invasion and metastasis-related proteins, such as matrix metalloproteinase-9 (MMP-9) and urokinase-type plasminogen activator (uPA), in NSCLC-bearing mouse models. Additionally, fluoxetine activated apoptotic-related proteins caspase-3, -8, and -9 in CL-1-5/F4 cells to trigger extrinsic/intrinsic apoptotic signaling and inhibit tumor growth.
  3. SNRIs antidepressant drugs
    SNRIs are another important class of antidepressants, such as duloxetine, venlafaxine, and the novel ansofaxine43. SNRIs inhibit the reuptake of both 5-HT and NE, potentially exerting more complex effects on tumors closely related to the NE signaling pathway44. While some studies suggest a possible increase in lung cancer risk, some studies indicate that SNRIs have good efficacy in lung cancer-depression comorbidity patients45,46.
    For NSCLC patients carrying EGFR mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the standard first-line treatment. However, most patients often develop clinical resistance. Duloxetine is commonly used to treat chemotherapy-induced peripheral neuropathy47. A prospective, randomized, open-label study demonstrated that duloxetine effectively treats neuropathic pain in lung cancer patients and is well-tolerated48. In recent years, duloxetine has been found to exhibit anti-proliferative effects in pancreatic cancer cells through modulation of immune and inflammatory conditions. A pivotal 2024 study by Jang et al.49 provided crucial mechanistic insights into how duloxetine enhances the efficacy of EGFR-TKIs in NSCLC, addressing both wild-type and mutant EGFR contexts. The research demonstrated that duloxetine, uniquely among SNRIs tested (including milnacipran, venlafaxine, and desvenlafaxine), synergistically induced cell death when combined with EGFR-TKIs (lapatinib, gefitinib, erlotinib) across multiple NSCLC cell lines (H1299, H460, A549). Mechanistically, duloxetine was found to activate the ATF4/REDD1 signaling axis, leading to the suppression of the mTORC1/S6K1 pathway-a key driver of tumor growth and a known resistance mechanism to EGFR-TKIs. This effect was confirmed in REDD1-knockout and ATF4-knockdown models, where the synergistic cell death was significantly attenuated. Importantly, the study included the EGFR-TKI-resistant cell line H1975, which harbors the EGFR L858R/T790M double mutation. Duloxetine significantly enhanced the sensitivity of these resistant cells to EGFR-TKIs, inducing approximately 50% more cell death in combination therapy compared to either agent alone, while other SNRIs showed minimal effect. This identifies a potential "effective population subgroup" for duloxetine combination therapy: NSCLC patients, including those with acquired T790M-mediated EGFR-TKI resistance, where targeting the ATF4/REDD1/mTORC1 axis could overcome therapeutic resistance49.
    In addition, a study published in 2025 comprehensively evaluated ansofaxine in a mouse model of lung cancer combined with depression50. The results indicated that compared to fluoxetine and venlafaxine, ansofaxine had superior effects in inhibiting lung cancer cell proliferation and promoting apoptosis. Ansofaxine, as a novel SNRI with triple reuptake inhibition (serotonin, norepinephrine, and dopamine), demonstrates unique pharmacological properties. Ansofaxine not only effectively reversed the immune suppression state in the depression model mice (significantly increased CD8+ T cell proportion, decreased Tregs proportion) but also restored levels of serotonin (5-HT) and norepinephrine (NE) in the serum while reducing the stress hormone cortisol. When combined with triple immunotherapy (anti-PD-1, anti-TNFR2, anti-PTP1B), the survival rate of mice in the ansofaxine group significantly increased, and the expression of PD-L1 and TNFR2 in tumor tissues also significantly decreased. This indicates that ansofaxine possesses not only direct antitumor and immune regulatory activities but also effectively sensitizes immune checkpoint inhibitors (ICIs), demonstrating significant potential as an ideal choice for lung cancer patients with comorbid depression.
    Safety considerations and limitations
    The use of antidepressants in lung cancer patients requires careful consideration of potential adverse effects and drug interactions. TCAs may cause anticholinergic effects51, while MAOIs have numerous drug interactions with anticancer medications52,53. SSRIs and SNRIs are generally better tolerated but may still interact with certain chemotherapeutic agents or targeted therapies through pharmacokinetic pathways such as CYP450 enzyme modulation, which may affect drug metabolism and efficacy27,37. Close monitoring for side effects and individualizing treatment choices are essential. Current evidence has several limitations, including overrepresentation of preclinical studies, lack of standardized diagnostic tools for depression in cancer populations, heterogeneity in treatment regimens and follow-up duration, and limited long-term survival data from clinical studies.

Conclusions

Depression accelerates lung cancer progression through chronic activation of neuroendocrine and inflammatory pathways, while antidepressants may counter these effects by restoring immune balance and promoting apoptosis (Figure 1). Through sustained activation of the HPA axis and SNS, depression leads to high levels of cortisol and catecholamines that directly promote tumor cell proliferation and systematically reshape the tumor immune microenvironment, resulting in impaired CD8+ T cell function and Treg expansion (Table 1). This reduces antitumor immunity and may decrease the efficacy of immunotherapies such as ICIs.

Although antidepressant drugs of different classes act on diverse targets and pathways, they share common antitumor mechanisms: (1) Induction of cell apoptosis and autophagy through Bcl-2 family, Caspase cascades, mTOR, and MAPK pathways; (2) Modulation of the tumor immune microenvironment by regulating neurotransmitter levels (5-HT, NE), inhibiting immunosuppressive molecules like IDO, and improving TME composition; (3) Impact on cell metabolism by interfering with mitochondrial function and oxidative stress levels.

Clinical and translational implications
These neuroendocrine and immune mechanisms suggest antidepressant therapy could play a dual role in symptom relief and tumor modulation. This understanding could inform clinical practice by supporting the use of antidepressants as adjuvant therapies in oncology, particularly in patients with comorbid depression; monitoring neuroendocrine biomarkers (e.g., cortisol, BDNF) in treatment planning to guide personalized interventions; and implementing early psychological interventions to modulate tumor-promoting pathways, thereby potentially enhancing both quality of life and treatment outcomes.

Future directions:
Phase II trials evaluating fluoxetine or duloxetine combined with PD-1 inhibitors in NSCLC are warranted. Prospective studies stratifying antidepressant response by HPA axis activity or inflammatory cytokine profile would help personalize treatment. Exploration of biomarkers linking mood regulation and tumor response is encouraged.

Integrating psycho-oncological management into lung cancer care may not only improve quality of life but also enhance therapeutic efficacy through biological synergy.

Depression mechanisms vs. antidepressant effects diagram; tumor microenvironment influence pathways.
Figure 1: Bidirectional model of depression-driven lung cancer progression and antidepressant counteractions. Depression activates the HPA axis and SNS, releasing cortisol and catecholamines, which promote pro-inflammatory cytokine production (e.g., IL-6, TNF-α) and impair neuroplasticity via reduced BDNF/TrkB signaling. These changes lead to an immunosuppressive tumor microenvironment with increased Tregs, decreased CD8+ T cells and NK cells, and upregulation of IDO, PD-L1, and VEGF, ultimately enhancing tumor proliferation, invasion, and apoptosis resistance. Antidepressants (SSRIs, SNRIs) inhibit reuptake of 5-HT and NE, leading to immune enhancement, restored BDNF signaling, reduced inflammation, and direct antitumor effects via apoptosis induction and autophagy regulation. Arrows indicate activation (solid) or inhibition (dashed). Feedback loops include cytokine enhancement of HPA activation and antidepressant reduction of cytokine output. Please click here to view a larger version of this figure.

Mechanism CategoryKey Molecules/PathwaysDepression EffectsAntidepressant Counteractions
Neuroendocrine AxisHPA axis (cortisol), SNS (NE, E), β-adrenergic receptors↑ Cortisol → immune suppression; ↑ NE/E → tumor proliferation via PKA/MAPKNormalize HPA/SNS activity; reduce stress hormone levels
Inflammatory SignalingIL-6, TNF-α, IL-1β, CRP, IDO, PD-L1, CTLA-4↑ Pro-inflammatory cytokines; ↑ immunosuppressive cells (Tregs, MDSCs); ↓ CD8+ T cells/NK cells↓ Pro-inflammatory cytokines; ↑ CD8+ T cells; ↓ Tregs; modulate IDO activity
Lung-Brain AxisBDNF, TrkB, PI3K/AKT, RAS/ERK, JAK/STAT↓ BDNF/TrkB signaling → impaired neuroplasticity; altered peripheral TMERestore BDNF/TrkB signaling; modulate neurotrophic factors
Apoptosis/AutophagyBcl-2, Caspases, DR5/TRAIL, ATF4-AKT-mTOR, LC3B, p62↑ Apoptosis resistance; altered autophagy↑ Apoptosis via Caspase activation; modulate autophagy flux
Immune Modulation5-HT, SERT, NET, CD8+ T cells, Tregs, PD-1/PD-L1Altered neurotransmitter levels; immune dysregulation↑ 5-HT/NE via SERT/NET inhibition; enhance T cell function; sensitize to ICIs

Table 1: Key mechanisms linking depression to lung cancer progression and antidepressant counteractions. This table summarizes the major biological pathways involved in the depression-cancer relationship and the corresponding mechanisms through which antidepressants may exert protective effects. HPA: hypothalamic-pituitary-adrenal; SNS: sympathetic nervous system; NE: norepinephrine; E: epinephrine; IL: interleukin; TNF-α: tumor necrosis factor-alpha; CRP: C-reactive protein; IDO: indoleamine 2,3-dioxygenase; BDNF: brain-derived neurotrophic factor; TrkB: tropomyosin receptor kinase B; TME: tumor microenvironment; Tregs: regulatory T cells; MDSCs: myeloid-derived suppressor cells; 5-HT: serotonin; SERT: serotonin transporter; NET: norepinephrine transporter; ICIs: immune checkpoint inhibitors.

Disclosures

The authors declare no conflict of interest.

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Depression ProgressionHypothalamic Pituitary AdrenalSympathetic Nervous SystemCytokine InflammationLung Brain AxisBDNF TrkB SignalingAntidepressant TherapyChronic Stress PathwaysImmune Modulation

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