COVID-19 and Lung Cancer Interactions: A Literature Review.

1. Introduction
The COVID-19 pandemic triggered a sudden and profound disruption of oncology services worldwide, with multiple population-based registries documenting drastic declines in cancer diagnoses during 2020–2022 [1,2]. Among the conditions most visibly affected was lung cancer (LC), which remains the leading cause of cancer-related death worldwide, accounting for approximately 1.8 million deaths annually [2,3,4,5,6,7,8,9] (Table 1). In the first pandemic year, several independent national and regional cancer registries reported striking reductions in incident lung cancer diagnoses compared with 2019, with estimates ranging from a 10 to 20% decline in overall case numbers in the United States, United Kingdom, Italy, Poland, and Japan [5,6,7,8,9].
These incidence troughs coincided with health-system reorganization, curtailed elective imaging, restricted aerosol-generating diagnostics such as bronchoscopy, and widespread patient avoidance of healthcare settings. The phenomenon was a “diagnostic deficit” rather than a true fall in carcinogenesis [10,11,12,13,14,15,16]. In accordance with this interpretation, datasets from the United States, Europe, and Asia report stage migration toward advanced disease without commensurate reductions in mortality, implying delayed recognition of early-stage tumors that typically confer curative opportunities [15,17,18,19,20,21,22,23] (Figure 1).
Beyond service disruption, SARS-CoV-2 biology plausibly intersects with lung oncogenesis through host–virus pathways that regulate epithelial injury, inflammation, and immune surveillance [24,25,26,27,28,29,30]. Viral entry via ACE2 and priming by TMPRSS2 initiate a replication program, the proteins of which modulate autophagy, inflammasome activation, and antigen presentation. These mechanisms may be linked to tumor promotion and immune evasion in thoracic oncology [24,25,31,32,33,34,35,36,37,38,39,40,41]. Acute COVID-19 features an imbalanced host response marked by elevations of IL-1β, IL-6, IL-8, TNF-α and interferon-inducible chemokines (e.g., CXCL9/CXCL10) that govern myeloid recruitment, T-cell positioning, angiogenesis, and tissue remodeling. These axes have established roles in lung-cancer progression and checkpoint responsiveness [39,40,41,42,43,44,45,46,47,48,49,50,51,52]. Long COVID further reveals persistent innate activation and cytokine/chemokine dysregulation, including the IL-1β/IL-6/TNF-α triad and perturbations in CCL2, CCL5, and CXCL9. These changes also raise the possibility that chronic post-viral inflammation could condition pro-tumor microenvironments in susceptible hosts [53,54,55,56,57,58,59,60,61,62,63,64,65].
At the same time, current population-level analyses largely attribute pandemic-era incidence fluctuations to diagnostic backlogs and reporting dynamics rather than to virus-driven changes in tumor initiation, highlighting a critical need to disentangle service-delivery artifacts from any genuine biological effects [5,6,15,17,21,66].
This review presents and synthesizes data evidence across epidemiology as published by the Global Burden of Disease 2019 Cancer Collaboration, Global Cancer Statistics (GLOBOCAN), the International Agency for Research on Cancer (IARC), and the International Association of Cancer Registries (IACR) for virology, lung-cancer pathogenesis, immune-checkpoint biology, acute and post-acute immune dysregulation, and hypothesized oncogenic mechanisms of SARS-CoV-2 as published between 2019 and 2025 [5,7,17,20,45,46,47,48,67,68,69,70,71]. We aim to discuss whether observed declines in lung-cancer diagnoses predominantly reflect temporary diagnostic disruption or reveal deeper intersections between COVID-19 and pulmonary oncogenesis with implications for screening, diagnosis, and therapeutic strategy.

2. The Observed Effect of the COVID-19 Pandemic on Cancer Incidences
The onset of the COVID-19 pandemic in early 2020 was associated with an abrupt global decline in newly diagnosed cancer cases, a trend documented across multiple national cancer registries and hospital networks [5,6,7,8,9,13,14,15]. In the United States, analysis of the U.S. Cancer Statistics dataset covering nearly 97% of the population demonstrated a 13.6% reduction in age-adjusted lung cancer incidence between 2019 and 2020, falling from 47.9 to 41.4 cases per 100,000 [17]. Importantly, this reduction was accompanied by a relative increase in late-stage diagnoses, consistent with delayed recognition of early-stage disease rather than a true fall in occurrence [17,18].
Similar disruptions were reported across Europe. In the United Kingdom, urgent cancer referrals dropped by more than 60% in April 2020, coinciding with the suspension of routine imaging and drastic reductions in bronchoscopy volumes [18,19]. LC was particularly affected because its diagnostic pathway relies heavily on chest radiography, CT scans, and invasive procedures that were deprioritized due to their aerosol-generating potential [10,16,19]. In Italy, registry data documented a marked decline in LC diagnoses during 2020, with stage shifts toward more advanced disease [20]. Polish and Scandinavian registries reported comparable deficits, highlighting that the problem was not limited to a single healthcare system but represented a widespread phenomenon [21,72].
In Japan, nationwide surveys showed reductions in cancer surgeries, diagnostic imaging, and pathology-confirmed lung cancer cases, again concentrated in early stages [73]. In South Korea, where public health controls limited healthcare disruption, the decline in new cancer diagnoses was smaller but still measurable, suggesting that more effort is required to prevent diagnostic deficits [74].
Canadian and U.S. community oncology networks also described a collapse in pathology report volumes and delayed treatment initiation, with LC showing among the steepest deficits [15,75].
The diagnostic deficit did not recover, despite the substantial reduction in anti-epidemiologic measures immediately post-pandemic (Figure 2).
The Romanian experience mirrored these international trends but was even more pronounced due to structural vulnerabilities in the healthcare system. During 2020, the addressability of patients to medical services fell drastically, driven both by fear of SARS-CoV-2 infection and by the reorganization of hospitals into COVID-only facilities. Reports from pulmonology departments indicated that bronchoscopy services were almost entirely suspended nationwide, as the procedure was considered high risk for aerosol generation and viral spread [16]. This meant that for much of the first pandemic year, patients with suspicious radiological findings had no access to diagnostic confirmation, creating a near-collapse in the LC diagnostic pipeline. Even in tertiary centers, bronchoscopy lists were reduced to emergency procedures, and the majority of suspected cases were deferred indefinitely [16,76]. As a result, Romanian oncologists observed substantial reductions in new LC case reporting during 2020–2021, consistent with the “diagnostic deficit” phenomenon described elsewhere.
Globally, several consistent patterns emerge. First, the temporal nadir in cancer diagnoses closely matched the timing of lockdowns, healthcare reorganizations, and procedural suspensions [13,18,20]. Second, the deficit was disproportionately concentrated in early-stage and screen-detected cancers, while symptomatic late-stage cases were more likely to still present, producing a relative enrichment of advanced disease in 2020 datasets [15,17,21]. Third, despite partial recovery of case numbers that occurred in 2021, the rebound was incomplete, and there was no compensatory overshoot in diagnostic activities to account for the missing cohort of 2020 cases (Figure 3) [13,21,72].
Healthcare system analyses attribute these trends to several converging mechanisms: suspension of elective imaging and procedures, reallocation of oncology staff to COVID-19 wards, reduced operating room capacity for cancer surgery, and patient-level avoidance of healthcare settings due to fear of contagion [10,11,12,13,19].
The implications for survival outcomes are significant. Modeling studies suggest that even a three-month diagnostic delay can reduce LC survival by allowing stage progression. Furthermore, widespread year-long diagnostic deficits are expected to translate into measurable increases in cancer mortality in the coming decade [22,67]. Some analyses [14,17,23] estimate that the combined effects of diagnostic delays and treatment interruptions could result in thousands of excess overall cancer deaths across Europe and North America, with LC contributing disproportionately due to its rapid natural history.
Indeed, the convergence of data across continents, including the USA, Romania, Scandinavian countries, Italy, Japan, and the UK, provides compelling evidence that the pandemic precipitated a global diagnostic deficit, sharply reducing observed LC incidence in 2020 while paradoxically worsening prognosis [5,7,16,17,18,21].

3. SARS-CoV-2 Infection, Transmission, Replication–Transcription, Proteins, and Treatment
SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA beta coronavirus whose entry into human cells is mediated primarily by the spike (S) glycoprotein engaging the angiotensin-converting enzyme 2 (ACE2) receptor [24,31,32]. Cryo-EM and crystallographic studies resolved the prefusion trimeric S architecture and the receptor-binding domain (RBD) complexed with ACE2, establishing the structural basis for high-affinity attachment and conformational transitions required for membrane fusion [31,32].
Following receptor engagement, S is primed by host proteases (notably TMPRSS2 and cathepsins) to trigger fusion at the plasma membrane or within endosomes, initiating cytosolic release of the ~30 kb RNA genome [24].
Once internalized, the viral replicase is translated from the genomic RNA to yield polyproteins pp1a/pp1ab, which are cleaved by the main protease (Mpro/3CLpro) and papain-like protease (PLpro) into nonstructural proteins (nsps) that assemble the replication-transcription complex (RTC) [25].
The RTC forms on virus-induced double-membrane vesicles where RNA synthesis proceeds, producing negative-sense intermediates and a nested set of sub-genomic mRNAs that encode structural (S, E, M, N) and accessory proteins [24,25]. Host–virus interactome mapping has identified numerous cellular pathways hijacked by the RTC and accessory proteins, including translation control, vesicular trafficking, and innate immune sensing hubs [26] (Figure 4).
Multiple viral proteins actively remodel intracellular trafficking and degradative pathways to favor replication while dampening antigen presentation [24,26]; the accessory protein ORF3a inhibits autophagosome–lysosome fusion by interacting with the HOPS tethering complex (e.g., VPS39), thereby blocking autophagic flux and potentially prolonging survival of infected cells [33,34]. Nsp6 provokes NLRP3 inflammasome activation and pyroptosis via ATP6AP1 targeting, illustrating a direct link between specific viral components and inflammatory cell death programs [35,36]. ORF8 down-regulates MHC-I on the host cell surface, a strategy that impairs antigen presentation to CD8+ T cells and facilitates immune evasion [37,38].
The characteristic host response to acute SARS-CoV-2 infection features blunted type I/III interferon signals juxtaposed with exuberant pro-inflammatory cytokine and chemokine production [39,40]. Studies identified IL-6, IL-8 (CXCL8), and TNF-α as independent predictors of in-hospital mortality, underscoring their central role in COVID-19 pathophysiology and triage algorithms [41].
Meta-analyses and multicenter datasets further associate severe disease with elevations in CCL2/MCP-1, CXCL9/MIG, and CXCL10/IP-10, chemokines linked to monocyte and CXCR3+ T-cell trafficking that correlate with respiratory failure [42,43,44].
These inflammatory signatures converge with the cellular reprogramming described above, in which viral proteins alter autophagy, inflammasome activation, and antigen presentation, together shaping a permissive yet tissue-damaging milieu in the lung [33,34,35,36,37,38,39,40,42,43,44]. Beyond canonical cytokines, chemokine perturbations have mechanistic and therapeutic implications in COVID-19 and bear relevance for thoracic oncology [42,43,44]. Elevations of CCL2/MCP-1 reflect monocyte recruitment programs that are also prominent in tumor-associated macrophage (TAM) biology, suggesting shared axes of immune-cell trafficking in viral pneumonia and lung cancer microenvironments [42,45,46,77]. In severe COVID-19, increased CXCL9 and CXCL10 track with IFN-γ-driven inflammation and predict adverse trajectories, paralleling their known roles in orchestrating CXCR3+ effector T-cell positioning in tumors and responses to immune checkpoint blockade [42,43,44,47,48].
These overlaps between antiviral and antitumor chemokine networks provide a conceptual bridge for later sections examining immune-checkpoint dysfunction in lung cancer and the long-term immune dysregulation after SARS-CoV-2 infection [42,43,44,47,48].
Transmission dynamics of SARS-CoV-2 are driven by high viral loads in the upper respiratory tract and efficient droplet/aerosol spread, with peak infectiousness near symptom onset and in the presymptomatic window [31].
Although successive variants altered intrinsic transmissibility and immune escape, the fundamental entry, replication, and many antagonism strategies remained conserved, maintaining therapeutic relevance of targets such as Mpro and the viral polymerase (RdRp/nsp12) [24,25]. Therapeutic development rapidly translated mechanistic insights into effective antivirals and immunomodulators [24,25,26].
The ACTT-1 randomized trial showed that remdesivir, an RdRp inhibitor, shortened time to recovery among hospitalized adults with lower respiratory tract involvement versus placebo [78]. A large platform trial (RECOVERY) demonstrated that low-dose dexamethasone reduced 28-day mortality among patients requiring oxygen or mechanical ventilation, establishing corticosteroids as a standard of care for hypoxemic COVID-19 [79]. In critically ill patients, interleukin-6 receptor antagonists (tocilizumab or sarilumab) improved outcomes when added to standard care, supporting targeted cytokine modulation in hyperinflammation [80].
For outpatients at high risk of progression, oral nirmatrelvir–ritonavir (a potent Mpro inhibitor co-formulated with a pharmacokinetic enhancer) significantly lowered the risk of hospitalization or death when initiated early [81].
Finally, virally induced tissue remodeling may intersect with cancer risk biology, though definitive causal links remain unproven [24,27,39].
Reviews and hypothesis publications have posited that persistent inflammation, fibrosis, and ACE2 pathway perturbations could, in theory, influence carcinogenic processes in the lung. However, longitudinal population-level evidence directly tying SARS-CoV-2 infection to increased lung cancer incidence is currently lacking [27,28,29,30].
Given this uncertainty, it is essential to distinguish between the observed pandemic-era fall in lung cancer incidence due to diagnostic disruption and the speculative notion of virus-driven oncogenesis. This subject will be discussed again after detailing LC pathogenesis and immune dysregulation.

4. Pathogenesis of Lung Cancer

4.1. Driving Oncogenic Mutations Define the Histological Characteristics of the Tumor
LC encompasses histologically and molecularly distinct entities: predominantly non-small-cell lung cancer (NSCLC adenocarcinoma, squamous, and large-cell types) and small-cell lung cancer (SCLC), which arise through accumulated genomic alterations, epigenetic reprogramming, and selection within inflamed or injured lung microenvironments [82].
Comprehensive atlases delineate the recurrent driver-mutation landscape in NSCLC, with LUAD (Lung Adenocarcinoma) enriched for KRAS, EGFR, BRAF, MET exon 14 skipping, and kinase fusions (ALK, ROS1, RET), and LUSC (Lung Squamous Cell Carcinoma) dominated by TP53 loss, CDKN2A inactivation, SOX2/FGFR1 amplifications, and oxidative-stress pathway lesions (KEAP1–NFE2L2) [83,84].
Tobacco smoke produces characteristic cytosine-to-adenine base substitutions and a high tumor mutational burden, whereas never-smokers more often harbor oncogene-related LUAD with distinct etiologies, highlighting exposure–genotype interactions [85].
Environmental and occupational cofactors, including indoor radon, silica dust, asbestos, and ambient fine particulates (PM2.5), make independent contributions to LC risk beyond active smoking, with dose–response relationships documented in large cohorts and meta-analyses [86,87,88,89].

4.2. Co-Mutations Shape Immune Contexture and Therapy Response [82,83,84]
In KRAS-mutant LUAD, the co-loss of STK11/LKB1 or KEAP1 defines “immune-cold”, myeloid-skewed tumors with low PD-L1 and attenuated responses to PD-(L)1 blockade, a phenotype reproduced across retrospective cohorts and translational datasets. By contrast, KRAS tumors lacking these co-alterations more often exhibit inflammatory T-cell infiltration (“immune hot”) and can respond favorably to checkpoint inhibitors, underscoring the interaction between tumor-intrinsic circuitry and antitumor immunity [34,90].

4.3. Cytokine Signaling Is Integral to Lung Tumor Progression [82]
The IL-6–JAK–STAT3 pathway promotes survival, stemness, epithelial-to-mesenchymal transition (EMT), metabolic reshaping, and immunosuppression via induction of PD-L1 and myeloid recruitment programs, placing IL-6 at the nexus of cancer cell fitness and microenvironmental control [49]. IL-8/CXCL8, produced by tumor cells, fibroblasts, and myeloid cells, drives neutrophil chemotaxis, angiogenesis, and EMT, correlating with aggressive disease and resistance to targeted and immune therapies [50].
IL-1β licensing of myeloid cells fosters angiogenesis and suppressive macrophage/MDSC accumulation. Exploratory analysis of inhibition of IL1β by Canakinumab (CANTOS trial) has been shown to significantly reduce lung cancer incidence and mortality. The findings strengthen the mechanistic link between chronic IL-1 signaling and lung tumorigenesis, as suggested by delayed progression of diverse molecular subtypes of lung cancer subsequent to reduction in tumor-promoting inflammation [51,52].
TNF-α is pleiotropic in cancer but chronically activates NF-κB and AP-1 programs that support proliferation, invasion, and EMT, with context-dependent crosstalk that can tip inflammation toward tumor promotion [91].

4.4. Chemokine Circuits Orchestrate Cellular Traffic and Functional States in the Tumor Microenvironment
CCL2/CCR2 recruits inflammatory monocytes that differentiate into tumor-associated macrophages (TAMs), often assuming immunosuppressive, pro-angiogenic phenotypes that blunt cytotoxic T-cell control [45,46]. CCL5/CCR5 signaling is context-dependent, supporting CD4+/CD8+ recruitment under effective priming yet also attracting CCR5+ macrophages and Tregs that promote immune escape, helping explain heterogeneous correlations with outcomes across datasets [46,47,77].
Conversely, interferon-inducible CXCL9/CXCL10 guide CXCR3+ effector T cells into tumors and associate with benefit from PD-1/PD-L1 blockade in preclinical models and human translational studies, linking type-I/II interferon tone to checkpoint responsiveness [47,48].

4.5. Tissue Context Is Important for Tumorigenesis and Disease Progression
Patients with idiopathic pulmonary fibrosis (IPF) and other fibrotic interstitial lung diseases have a markedly increased incidence of lung cancer, illustrating how repetitive injury, aberrant repair, and profibrotic cytokines create permissive niches for oncogenesis that may be recapitulated after severe viral pneumonitis [92].
Because staging as part of diagnosis is the dominant determinant of treatment and subsequent survival in lung cancer, even brief perturbations to imaging and tissue acquisition (such as pandemic-era interruptions) translate into stage advancement and worse outcomes, independent of any change in the underlying rate of carcinogenesis [67,82].
In sum, lung cancer pathogenesis reflects the integration of carcinogen-driven genomics with inflammation-shaped microenvironment, wherein IL-1β, IL-6, IL-8, TNF-α, and chemokines CCL2, CCL5, CXCL9 tune angiogenesis, myeloid skewing, T-cell response positioning, EMT, and checkpoint responsiveness, providing multiple mechanistic bridges to the cytokine–chemokine perturbations observed in acute and post-acute COVID-19 [45,46,47,48,49,50,52,82,83,84,85,90,91,92]. Table 2 presents possible cytokine/chemokine functions in LC pathogenesis.

5. Dysfunction of the Immune System in Lung Cancer: The Role of Immune Checkpoints
Physiological immune checkpoints such as CTLA-4 and PD-1/PD-L1 enforce immune tolerance and limit tissue damage during inflammation and tissue repair. Tumors exploit these pathways to attenuate T-cell priming and effector function within the tumor microenvironment (TME) [91].
In NSCLC, treatments with monoclonal antibodies that block PD-1 or PD-L1 durably improve objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with standard platinum chemotherapy in biomarker-selected individuals [93,94,95,96,97]. First-line pembrolizumab significantly prolonged OS versus chemotherapy in metastatic NSCLC with PD-L1 tumor proportion score (TPS) ≥ 50%, with a 5-year OS rate of 31.9% versus 16.3% and sustained tolerability [93].
Dual checkpoint blockade with nivolumab plus ipilimumab improved OS and PFS compared with chemotherapy across PD-L1 strata in the CheckMate 227 trial, establishing CTLA-4 co-inhibition as a viable option for selected patients [94].
Atezolizumab monotherapy (IMpower110) extended OS in treatment-naïve metastatic NSCLC with high PD-L1 expression, confirming PD-L1 as an enrichment biomarker for anti-PD-(L)1 benefit [95].
Cemiplimab likewise improved survival in EMPOWER-Lung 1 for PD-L1 ≥ 50% NSCLC, with durable benefit in longer follow-up analyses [96,97] (Table 3).
Checkpoint expression is shaped by tumor-intrinsic oncogenic programs and inflammatory tone that govern antigenicity, interferon signaling, and myeloid composition [82,90]. KRAS-mutant LUAD co-altered by STK11/LKB1 or KEAP1 mutations exhibits a myeloid-dominant, “cold tumor” state with low PD-L1 and inferior responses to PD-(L)1 therapy [90].
Pro-inflammatory cytokines relevant to pulmonary oncology intersect with checkpoint pathways: IL-6 trans-activates JAK/STAT3 in lung cancer and can upregulate PD-L1, while EGFR signaling on tumor cells converges on the IL-6–STAT3 axis to enhance PD-L1 expression [98,99]. IL-8/CXCL8 promotes neutrophil influx and EMT and predicts checkpoint inhibitor treatment resistance. Experimental IL-8 blockade restores anti-PD-1 activity in preclinical models [100,101,102].
Type-II interferon (IFN-γ) inflammatory signaling induces PD-L1 expression on cancer cells, conducive for tumor immune evasion, and at the same time upregulates chemokines such as CXCL9/CXCL10 that recruit CXCR3+ effector T cells as a cytotoxic response to cancer [47,48].
Axes such as CCL2/CCR2 and CCL5/CCR5 regulate tumor-associated monocyte/macrophage (TAM) and regulatory T-cell (Treg) trafficking, often fostering immunosuppressive niches that hinder cytotoxic lymphocyte (CTL) function, whereas CXCL9/CXCL10 support CTL recruitment and are associated with benefit from PD-1/PD-L1 blockade [45,46,47,48] (Table 4).
Extensive checkpoint inhibition may cause immune-related adverse events (irAEs) that reflect systemic disinhibition of immune responses. Among pulmonary toxicities, checkpoint inhibitor pneumonitis (CIP) is uncommon but potentially life-threatening, with higher incidence in lung cancer patients and combination regimens [103,104,105,106]. Not surprisingly, radiological ground-glass opacities and organizing-pneumonia patterns predominate in CIP but overlap with viral pneumonias such as COVID-19, having exacerbated immune response as a common background and necessitating clinical and microbiologic adjudication and, when needed, bronchoscopy [107,108,109].
During the pandemic, imaging similarities between CIP and COVID-19 pneumonia complicated triage and management, prompting multidisciplinary algorithms incorporating exposure history, PCR testing, timing relative to ICI doses, and, when feasible, bronchoscopy with protected specimen collection [107,108,109].
Together, these data place immune checkpoints at the heart of lung cancer immune dysfunction—where cytokine/chemokine circuits (e.g., IL-1β, IL-6, IL-8, TNF-α; CCL2, CCL5, CXCL9) modulate T-cell responses, myeloid skewing, and PD1/PD-L1 regulation—and illustrate how pandemic-related diagnostic barriers intersected with an already complex immunobiology [45,46,47,48,90,93,94,95,96,97,98,99,100,101,102] (Figure 5).
Theoretically, the overlapping immunologic enhancement of COVID-19 infection and ICI therapy could result in an increase in immune-related adverse events (irAEs). A single-center study suggested that COVID-19 may pose a risk of severe irAEs in cancer patients receiving ICIs. Close monitoring and possibly delaying ICI administration could be considered when cancer patients are infected with COVID-19. The study included, besides NSCLC (the majority of the cases), other tumor types, including renal cell carcinoma, melanoma, hepatocellular cancer, endometrial cancer, and uterine cancer. The incidence of irAE was higher in COVID-19 positive patients (30.4% vs. 19.9%), but it was not statistically significant (p = 0.13). On the other hand, a significantly higher incidence of severe irAEs was noted in the COVID-19 group (10.9% vs. 3.2%, p = 0.02) [110]. In a different study that included 159 patients treated with ICIs, in which 52 patients (32.7%) were infected with COVID-19, the authors found the incidence of AEs was not increased in the COVID-19 positive group treated with either ICIs, chemotherapy, or targeted therapy (p = 0.22), and there was no apparent increased risk of irAEs in the COVID-19 infected patients [111].

6. Immune Dysregulation in Acute SARS-CoV-2 Infection
Acute COVID-19 is characterized by an imbalanced host response: attenuated type-I/III interferon signaling alongside exuberant pro-inflammatory cytokine and chemokine production that correlates with respiratory failure [39,40,41,43,44]. Key mediators include IL-6, IL-8 (CXCL8), TNF-α, and interferon-inducible chemokines (CXCL9/MIG, CXCL10/IP-10) that drive monocyte recruitment, neutrophil activation, and CXCR3+ T-cell trafficking into inflamed lungs [41,43,44]. High IL-6, IL-8, TNF-α, and CXCL10 identify high-risk trajectories and inform triage and monitoring strategies [41,43,44]. Clinically, these axes justify targeted therapies: low-dose dexamethasone to dampen host-mediated lung injury; IL-6 receptor antagonists in critically ill patients; and targeted antivirals (remdesivir, nirmatrelvir–ritonavir) to curb viral replication and reduce inflammatory burden [78,79,80,81].
Elevated CCL2/MCP-1 mirrors monocyte-mobilizing programs also implicated in tumor-associated macrophage biology, highlighting mechanistic overlaps between acute viral pneumonitis and cancer microenvironments [42,45,46].
Pathology and translational studies reveal diffuse alveolar damage coupled to pulmonary endotheliosis, platelet–fibrin microthrombi, and intussusceptive angiogenesis, distinguishing severe COVID-19 from typical ARDS and implicating immunothrombosis in hypoxemia [112,113,114].
Neutrophil extracellular traps (NETs) are markedly increased in severe disease and associate with thrombosis and organ damage, positioning NET-osis as a therapeutic target [115,116,117]. Complement activation contributes to microvascular injury, with deposition of C4d and C5b-9 in lung and cutaneous vessels in severe COVID-19 and broader evidence of complement–coagulation crosstalk [118,119,120].
Viral proteins interface with innate immunity to potentiate this inflammatory milieu [24,25,26,33,34,35,36,39]. Nsp6 triggers NLRP3-dependent pyroptosis via ATP6AP1 targeting, while ORF3a impairs autophagosome–lysosome fusion, thereby sustaining danger signaling and antigen persistence [33,35]. ORF8 down-regulates MHC-I, hindering antigen presentation to CD8+ T cells and blunting cytotoxic clearance of infected cells [37,38].
Collectively, acute COVID-19 generates a cytokine- and chemokine-rich environment (IL-1β, IL-6, IL-8, IL-17, TNF-α, CCL2, CCL5, CXCL9) that overlaps with lung-cancer-relevant circuits governing myeloid recruitment, T-cell positioning, angiogenesis, and tissue remodeling, setting the stage for the longer-term immune perturbations discussed next [42,43,44,45,46,47,48,49,50,51,52,115,116,117,118,119,120] (Figure 6).

7. Immune Dysregulation in Long COVID
Long COVID (post-acute sequelae of SARS-CoV-2, PASC) is characterized by persistent immune activation and a lack of coordinated adaptive responses months after infection [53]. Deep immunophenotyping demonstrates skewed T-cell subset distributions, an increase in CD4+ T cells with tissue-homing phenotypes, and exhausted SARS-CoV-2-specific CD8+ T cells in individuals with long COVID compared with convalescent controls [53].
These perturbations co-exist with higher anti-SARS-CoV-2 antibody levels and a miscoordination between virus-specific T- and B-cell responses, implying continued inflammatory stimuli or antigen persistence [53]. Furthermore, independent cohorts confirm that immunological dysfunction, including elevated inflammatory mediators and altered innate and adaptive immune cell populations, can persist for at least eight months following mild-to-moderate infection [54].
Multi-omic analyses during acute infection identify risk signatures for PASC, including SARS-CoV-2 nucleocapsid (N) protein antigenemia, RNAemia, specific autoantibodies, and herpesvirus (e.g., EBV) reactivation, which predict downstream immune dysregulation and symptom persistence [55].
Across studies, a reproducible cytokine signature featuring interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), the so-called “cytokine triad”, is associated with long COVID and correlates with ongoing symptom burden and distinguishes affected individuals from matched convalescent controls [56]. Subsequent longitudinal work supported persistent elevation of this triad months after infection and associated it with fatigue, exertional intolerance, and neurocognitive symptoms [57] along with immune cell phenotypes indicative of low-grade chronic inflammation [58,59,60].
Among well-established immune responses, Th17-mediated immunity appears variably engaged [121]. Some studies report that increased IL-17 family cytokines or Th17-skewing signatures in long COVID, especially in patients with neurocognitive symptoms, fatigue, or dysautonomia [121,122]. Importantly, reports of increased IL-17 (or IL-17F) are stronger in acute/severe COVID-19 and in analyses linking endothelial activation to persistent symptoms; nonetheless, causality for chronic pulmonary symptoms remains under study [123,124].
Chemokine axes that coordinate leukocyte trafficking also remain unsettled in long COVID [60]. Increased monocyte chemoattractant protein-1/CCL2 (MCP-1) has been observed in PASC cohorts, with some data suggesting later rises beyond one year in persistent cases [61]. The CCL2–CCR2 pathway is a recognized amplifier of COVID-19 lung inflammation during acute disease, and elevated CCL2 has been documented in respiratory specimens and blood of severe cases [62].
Reports in PASC also describe dysregulation of CCL5/RANTES and CXCR3 ligands (e.g., CXCL9/MIG), consistent with sustained trafficking signals for activated T cells and monocytes. Such patterns have been linked to symptom clusters and endothelial activation in post-COVID patients [60,63,64,65]. Machine-learning classifiers trained on cytokine/chemokine hubs (including CCL5 and IL-6) were shown to distinguish PASC from other chronic inflammatory conditions, underscoring the biologic specificity of these immune signatures [125].

8. Possible Oncogenic Mechanisms of SARS-CoV-2, Hypotheses and Evidence Gaps
No definitive epidemiologic evidence demonstrates that SARS-CoV-2 infection increases population-level LC incidence independent of diagnostic disruption, but multiple mechanistic hypotheses deserve careful evaluation [6,17,21,66]. On the other hand, SARS-CoV-2 proteins and host responses could intersect with the “hallmarks of cancer”, including sustained proliferative signaling, resistance to cell death, angiogenesis, immune evasion, and chronic inflammation [66,126,127].
At the tissue level, pulmonary imaging and physiology reveal persistent small-airways disease and gas-transfer impairment in symptomatic convalescents [128,129]. Quantitative expiratory CT analyses show air trapping consistent with distal airway dysfunction, often independent of initial acute severity [128]. Hyperpolarized xenon-129 MRI demonstrates persistent abnormalities in alveolar–capillary gas exchange among non-hospitalized individuals with dyspnea months after infection [129]. These physiologic alterations coexist with systemic inflammatory signatures, suggesting that ongoing epithelial–endothelial injury and aberrant repair may be sustained by the cytokine–chemokine environment described above [53,56,128,129] (Figure 7).
A leading, indirect pathway is inflammation-driven tumor promotion, particularly through IL-6/JAK–STAT3, IL-1β/NLRP3, TNF-α/NF-κB, and ELR+ CXC chemokines (e.g., IL-8/CXCL8), which are all engaged during COVID-19 and have established roles in lung tumor biology [68,69,70,71,98,99,101,105,112,130,131,132,133,134,135,136,137,138,139,140,141,142] (Table 5).
Synthesis of these data supports a model in long-COVID patients in which chronic innate activation (IL-1β, IL-6, TNF-α) and immune-cell trafficking (CCL2, CCL5, CXCL9) maintain a low-grade inflammatory state, superimposed on T-cell mis-coordination and exhaustion [53,56,59,60,61,65], while these patients exhibit long-term radiographic and functional alterations, with heterogeneous recovery trajectories over 6–12 months and beyond [154].
Persistent activation of these inflammatory pathways could plausibly modify lung cancer risk in susceptible hosts, even if direct causality has not been established [68,69,70,71,98,99,101,105,112].
SARS-CoV-2 may also modulate epithelial barrier repair and cell-intrinsic stress pathways relevant to oncogenesis [66,126]. Autophagy blockade by the viral accessory protein ORF3a impairs autophagosome–lysosome fusion, potentially increasing oxidative stress and cytoplasmic DNA accumulation that feed pro-tumor inflammatory circuits [33,155,156]. SARS-CoV-2 ORF8 downregulates MHC class I, and N-linked glycan interactions contribute to antigen-presentation interference, which in theory could transiently reduce immune surveillance against incipient transformed clones [37].
ACE2 downregulation during infection perturbs the renin–angiotensin system (RAS), tipping the balance toward angiotensin II/AT1R signaling that promotes fibrosis, oxidative stress, and pro-inflammatory cytokine production in the lung microenvironment [28,29].
Chronic fibrotic remodeling of lung parenchyma (i.e., idiopathic pulmonary fibrosis) is a recognized risk factor for lung cancer, suggesting that post-viral fibrosis, if durable, could indirectly raise risk in a subset of patients [92,131,157]. Radiology and functional imaging studies after COVID-19 document persistent small-airways disease and gas-transfer abnormalities consistent with ongoing epithelial–endothelial injury that might, over time, create a pro-carcinogenic niche in susceptible individuals [128,129,154].
A separate, contentious hypothesis is viral genome integration [132]. One in vitro study proposed LINE-1–mediated reverse transcription and rare integration of SARS-CoV-2 sequences into host DNA, which could, in principle, create insertional mutagenesis or aberrant transcripts [132]. However, multiple independent investigations using long-read and whole-genome sequencing found no convincing evidence of SARS-CoV-2 integration in patient tissues, arguing that such events, if they occur at all in vivo, are extremely rare and unlikely to influence oncogenesis or clinical testing [133,134,135,136]. Thus, current data support inflammation-facilitated and repair-mediated mechanisms rather than direct viral insertion as plausible drivers of any long-term cancer-modifying effects [66,126,127,139,140,141,142].

9. Therapeutic Implications
Host–tumor interface pathways perturbed in COVID-19 overlap with therapeutic axes in lung cancer [68,98,105,109,130]. IL-6/JAK–STAT3 inhibitors, IL-1 blockers, and strategies targeting CCR2/CCR5 are under investigation in oncology and may, with careful selection, have dual relevance in patients with prior severe COVID-19 and inflammation-dominated tumor microenvironments [68,139,147,148,149,150,158].
Conversely, immune checkpoint pathways central to lung cancer (PD-1/PD-L1, CTLA-4) show altered ligand/receptor expression during and after SARS-CoV-2 infection, raising conceptual questions about timing and dosing of immunotherapy in patients with recent COVID-19 or persistent immune activation [112,113].
An interesting but speculative hypothesis suggests that the nonspecific activation of the immune system after viral infections could produce an antitumor effect through several mechanisms, including the bystander effect and molecular mimicry. Historically, in anecdotal cases, severe viral infections with high fever have been associated with spontaneous cancer remission, a phenomenon that has informed the development of modern immunotherapies using oncolytic viruses.
The hypothetical mechanism can be attributed to a robust tumor bystander T-cell response generated against a viral infection. The response is initially non-specific, receptor independent and cytokine-mediated (i.e., IFN gamma) that triggers tumor antigen release, and/or converts a “cold” tumor into a “hot” tumor type with the newly expanded CTL infiltration.
The cell-mediated antiviral response could become cross-reactive, meaning the T cells also recognize and attack tumor cells that express a similar-looking antigen or fragments. The neoantigenic recognition and activation in such events could theoretically result in long-term protection against cancer by creating an immunological memory that recognizes tumor-associated antigens. At the same time, cross-reactive antigenic viral fragments could be a source of post-viral autoimmune responses.
Despite the possibility of antitumor effects, the therapeutic benefits of viral infection are not guaranteed and can be unpredictable [159] (Figure 8).

10. Discussion
Across registries and health-system cohorts, the temporal signature of LC diagnoses—a steep minimum in 2020 aligned with lockdowns, procedure suspensions, and patient avoidance—together with stage migration toward advanced disease, indicates that the observed incidence dip is chiefly a diagnostic artifact, not a true biologic suppression of carcinogenesis [4,6,8,160]. This pattern holds across the United States, United Kingdom, Italy, Poland, Scandinavia, Japan, Canada, and is mirrored in Romania, where professional guidance restricted bronchoscopy and addressability plummeted, underscoring common mechanisms with local nuances [4,8,10,11,12,17,18,19,72,160]. Health-services analyses implicate curtailed imaging, reallocated staff, reduced endoscopy/bronchoscopy throughput, and fear-driven care deferral, with incomplete rebounds in 2021 and no compensatory overshoot, implying that some “missing” early-stage cancers were never recaptured in registry counts [2,5,7,10,72].
However, SARS-CoV-2 biology plausibly intersects with lung cancer pathways via ACE2/RAS, autophagy/lysosomal stress, inflammasomes, and immune checkpoint circuits, with IL-1β, IL-6, IL-8, IL-17, TNF-α, CXCL9, CCL2, and CCL5 as shared effectors shaping both acute COVID-19 and lung tumor microenvironments [6,7,8,18,33,67,73]. In acute infection, these mediators track with severity and outcomes and provide targets for effective therapies (e.g., dexamethasone, IL-6R blockade) that reduce hyperinflammation, while oral antivirals lower progression risk and viral burden [35,36,37,38,39,46,47].
In Long COVID, persistent cytokine/chemokine dysregulation, T-cell exhaustion, monocyte activation, and fibrotic remodeling present credible pathways by which host immunity and tissue context could be tilted toward protumor states in vulnerable lungs, though rigorous epidemiology remains pending [6,7,8,9,17,20,73].
Medical practice implications follow on two fronts:
First, health-system recovery: prioritize catch-up low-dose radiological screening for eligible populations; restore and protect bronchoscopy capacity with optimal personal protection equipment and airflow; streamline rapid diagnostic pathways; and deploy equity-focused outreach to communities with the largest diagnostic shortfalls [10,13,17,18,19].
Second, updated research agenda: link infection history and vaccination status to cancer registries; embed biospecimen collection (airways and serum) in post-COVID cohorts; profile ACE2/RAS, autophagy/lysosome, NLRP3, and checkpoint axes; and validate cytokine/chemokine signatures (IL-6, IL-1β, IL-8, IL-17, TNF-α, CXCL9, CCL2, CCL5) as risk stratifiers or therapeutic adjuncts in pulmonary oncology [19,24,31,33,67].
These steps will differentiate diagnostic backlog from true biologic effects of respiratory infections, detect and quantify associated long-term risks, and ensure resilient cancer control during epidemic outbreaks.

11. Conclusions
The pandemic and post-pandemic decline in observed lung cancer diagnoses in 2020 is best explained by the indisputable health-system disruption, as substantiated by the advanced-stage diagnostic shift and incomplete rebounds to the pre-pandemic status quo, signaling a substantial diagnostic debt that threatens outcomes in the registered incidence and mortality of lung cancer [4,5,6,160].
Mechanistic plausibility exists for SARS-CoV-2 to modulate tumor–host ecosystems through fibrosis, persistent cytokine/chemokine dysregulation, and autophagy/antigen-presentation stress as a substrate for accelerated oncogenesis [19,24,31,33,67], not a reduction in oncogenesis.
The non-specific activation of bystander cellular immunity components and suppression of inhibitory immune circuits by SARS-CoV-2 (as well as other respiratory viral infections) that may resolve very early tumorigenic stages is a speculative hypothesis and requires substantial clinical and basic research data to be sustained.
The shared inflammatory circuits of viral infections and cancer warrant additional exploration. Multi-omics analyses and machine learning algorithms using accumulated data from multiple research institutions may elucidate whether, and how, COVID-19 shapes pulmonary oncogenesis over time.
From a public-health perspective, the anticipation of potential diagnostic deficits in lung cancer should be carefully considered for the potential downstream effects when considering the duration and structure of the quarantine protocols. After extensive quarantines for viral respiratory infections, such as those imposed during the COVID-19 pandemic, public health systems should support specialty clinicians to accelerate catch-up screening, safeguard diagnostic throughput, and maintain vigilant monitoring for inflammatory lung sequelae.