Abstract
In the post-COVID-19 era, understanding the long-term impact of Long COVID on the immune system is essential for deciphering its influence on lung cancer pathogenesis and immunotherapeutic efficacy. This review comprehensively examines how persistent COVID-19 sequelae-manifested as chronic inflammation, pulmonary fibrosis, cytokine dysregulation, and T-cell exhaustion can reshape the lung cancer microenvironment. In addition, the emerging roles of memory B cells and altered neutrophil function in promoting tumorigenesis are discussed. Importantly, we analyze recent clinical evidence suggesting that COVID-19 vaccination may enhance the efficacy of immune checkpoint inhibitors, potentially by modulating host immunity. By integrating mechanistic insights with clinical observations, this review aims to illuminate the challenges and opportunities at the intersection of Long COVID and lung cancer treatment, thereby fostering the development of personalized therapeutic strategies in the post-pandemic era.
1 Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic emerging in late 2019, is a positive-sense, single-stranded RNA virus with a genome size of approximately 26–32 kb. Unlike retroviruses, the SARS-CoV-2 genome lacks a reverse transcriptase gene (). Viral entry into host cells is primarily mediated by the interaction between the receptor-binding domain (RBD) within the S1 subunit of its spike (S) glycoprotein and the host cell receptor angiotensin-converting enzyme 2 (ACE2) (Zhang H. et al., 2020). Clinically, SARS-CoV-2 infection manifests with a broad spectrum of symptoms, ranging from fever, cough, and headache to fatigue, anosmia, and diarrhea (). While most individuals recover from the acute phase of infection, a substantial subset experiences a persistent constellation of debilitating symptoms collectively termed post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as “Long COVID.” Key features include profound fatigue, persistent respiratory difficulties, evidence of pulmonary fibrosis, and diverse neurological dysfunction (). Critically, emerging evidence indicates that the immune dysregulation and chronic inflammation associated with Long COVID may exert downstream effects on tumorigenesis, potentially elevating cancer risk.
Concurrently, immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, demonstrating significant improvements in survival outcomes for patients with lung cancer (). Immune checkpoints are inhibitory surface receptors expressed on T cells and other immune cells, functioning as critical negative regulators of immune activation against various antigens, including tumor-associated antigens (). ICIs constitute a class of therapeutic monoclonal antibodies designed to block these inhibitory pathways, thereby removing barriers to T cell activation and harnessing the body’s intrinsic immune response against malignant cells (). Among the most intensively studied pathways in lung cancer immunotherapy are the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway (). Monoclonal antibodies targeting PD-1, CTLA-4, or PD-L1 have undergone extensive evaluation in advanced clinical trials. Substantial evidence confirms the promising clinical efficacy of ICI monotherapy and highlights the potential for synergistic effects in combination strategies for lung cancer treatment ().
Recent research has increasingly focused on the profound and lasting impact of Long COVID on the host immune system. The immune response is broadly categorized into the innate and adaptive arms, which function interdependently. An effective defense against SARS-CoV-2 necessitates coordinated activity from both systems (). The innate immune system includes granulocytes, monocytes, macrophages, natural killer (NK) cells, and dendritic cells, while the adaptive immune system relies on antigen-specific T cells and B cells (). A growing body of evidence indicates that Long COVID is characterized by significant immune alterations, prominently featuring T-cell exhaustion () alongside functional impairments in neutrophils () and B cells (). Notably, in severe acute COVID-19, dysregulated immune activation can culminate in a life-threatening “cytokine storm” (). In the post-COVID-19 era, understanding the specific and long-term consequences of Long COVID on the host’s immune system is paramount, particularly for lung cancer patients receiving ICIs, whose treatment efficacy hinges on a functional immune system.
This review explores the emerging intersection between Long COVID and lung cancer, framing a novel perspective on how the persistent immune dysregulation following SARS-CoV-2 infection could contribute to long-term oncogenesis. Specifically, we examine how immunological changes such as T cell exhaustion, cytokine dysregulation, and pulmonary fibrosis in Long COVID may affect the tumor microenvironment and immunotherapeutic efficacy in lung cancer. By synthesizing existing mechanistic studies and experimental data, this report elucidates the potential mechanisms of interaction between the altered immune system in Long COVID and lung cancer immunotherapy, providing a basis for future clinical and research strategies.
2 The association between long COVID and the incidence of lung cancer
Accumulating epidemiological evidence points to a significant association between SARS-CoV-2 infection and an elevated risk of lung cancer development, particularly among individuals experiencing persistent symptoms following prolonged COVID-19 infection. This potential link has garnered increasing attention within the medical research community (). Notably, cancer patients themselves exhibit heightened susceptibility to SARS-CoV-2 infection and experience poorer clinical outcomes. This susceptibility and prognostic significance are primarily reflected in increased mortality risk (), more severe clinical manifestations (), and a higher likelihood of infection (). This section delineates the postulated mechanisms underpinning the potential association between Long COVID and lung carcinogenesis.
2.1 Post-infection pulmonary complications and fibrosis
Substantial evidence indicates that SARS-CoV-2 infection can lead to long-term pulmonary complications (). Longitudinal studies tracking recovered patients for up to 15 years reveal chronic lung involvement characterized by persistent interstitial abnormalities detectable years post-infection (Zhang P. et al., 2020). Imaging analyses further demonstrate that a significant proportion (approximately one-third) of recovered patients exhibit radiological signs suggestive of pulmonary fibrosis (). Recently, several researchers proposed that pulmonary fibrosis may be a potential long-term complication associated with COVID-19 (). Critically, a well-established body of research directly links pulmonary fibrosis with an increased risk of lung cancer, with reported prevalence rates ranging from 2.7% to 48% among patients with idiopathic pulmonary fibrosis (). The fibrotic microenvironment induced by Long COVID may thus provide a fertile ground for lung cancer initiation and progression (Figure 1).
Figure 1
2.2 Chronic inflammation and cytokine dysregulation
Chronic inflammation is a widely recognized critical driver of carcinogenesis across multiple cancer types (; ), significantly contributing to tumor initiation, promotion, and progression (; ). In the context of Long COVID, the pulmonary milieu is often characterized by a sustained inflammatory state. This persistent inflammatory microenvironment may foster conditions conducive to lung carcinogenesis. Key inflammatory pathways implicated include the IL-6 amplifier mechanism, involving STAT3 activation by IL-6 and NF-κB activation by IL-17 or TNF-α (). These cytokines are known to play significant roles in tumor promotion and cellular transformation within lung cancer pathogenesis (; ). SARS-CoV-2 infection can trigger a profound release of pro-inflammatory cytokines, often termed a “cytokine storm,” with IL-6 frequently identified as a central mediator (; ; Yang et al., 2021). Furthermore, the clinical relevance of this axis is underscored by studies demonstrating reduced mortality in critically ill COVID-19 patients treated with IL-6 receptor antagonists, highlighting the pivotal role of cytokine dysregulation in disease severity and potentially long-term sequelae (; ; Zhou and Price, 2020) (Figure 1).
2.3 Dysregulation of the renin-angiotensin-aldosterone system
The renin-angiotensin-aldosterone system (RAAS) is crucial for chronic blood pressure and vascular resistance regulation. Components of this system, particularly angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang (1-7)], and angiotensin II (Ang-II), have been increasingly implicated in the progression of various malignancies, including from early stages (). Ang-II, a key effector peptide, has been associated with carcinogenesis, metastasis, and recurrence, potentially through mechanisms involving cancer stem cell formation (). In non-small cell lung cancer (NSCLC), Ang-II modulates cancer cell invasiveness and cancer stem cell populations (). Furthermore, high ACE2 expression has been proven to be correlated with malignancy and poor prognosis in certain cancers (Xu et al., 2017). SARS-CoV-2 utilizes ACE2 as its primary cellular receptor for entry. Infection leads to ACE2 downregulation, disrupting the balance between the pro-inflammatory/pro-fibrotic Ang-II/AT1R axis and the counter-regulatory Ang (1-7)/MasR axis. This RAAS dysregulation, a hallmark of both severe COVID-19 and Long COVID, may represent another pathway linking persistent infection to an altered lung microenvironment favoring tumorigenesis (; ) (Figure 1).
3 Shared mechanistic pathways linking long COVID and lung cancer
3.1 Chronic inflammation and cytokine storm
Persistent inflammation, characterized by elevated levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), is a hallmark of Long COVID (; ). Similarly, chronic inflammation is a well-established driver of lung cancer development and progression (). In Long COVID, sustained cytokine production can lead to immune cell dysfunction, tissue damage, and altered cellular signaling, potentially creating a permissive environment for malignant transformation or promoting the growth of pre-existing cancerous cells. Quantitatively, studies have shown that patients with severe Long COVID exhibit a 2–3 fold increase in IL-6 levels compared to recovered individuals without persistent symptoms ().
3.2 Immune dysregulation and T cell exhaustion
Both Long COVID and cancer are associated with profound alterations in immune cell function, including T cell exhaustion, increased expression of immune checkpoint molecules (PD-1, CTLA-4), and impaired antigen presentation (; ). In Long COVID, chronic antigen stimulation and inflammation can drive T cell exhaustion, reducing their ability to effectively eliminate infected or transformed cells. This immune dysfunction can also impair the efficacy of cancer immunotherapies. For example, PD-1 expression on CD8+ T cells is significantly higher in Long COVID patients compared to healthy controls (p<0.05) ().
3.3 Tissue remodeling and fibrosis
Pulmonary fibrosis is a significant concern in Long COVID patients, with some studies reporting fibrosis in up to 38% of severe cases (). Fibrosis alters the lung architecture, disrupts immune cell trafficking, and promotes the release of pro-tumorigenic factors, such as TGF-β (Wynn et al., 2008). The altered extracellular matrix can also hinder drug delivery and reduce the effectiveness of immunotherapies.
4 Immunopathology of long COVID: reshaping the lung cancer microenvironment
Long COVID is associated with profound and persistent alterations in immune cell composition and function. Studies report significant increases in neutrophils, monocytes, NK cells, and CD4+ T cells in Long COVID patients, alongside decreases in total lymphocytes and CD8+ T cells. Cytokine profiling reveals significantly elevated levels of IL-6, TNF-α, IFN-γ, IL-2, IL-4, and IL-10 in hospitalized patients, suggesting potential skewing of CD4+ T cell differentiation (). This section explores how key immunological features of Long COVID-T cell exhaustion, persistent memory B cell responses, and neutrophil extracellular trap (NET) formation – may impact the lung cancer immune microenvironment (summarized in Figure 2 and Table 1).
Figure 2
Table 1
| Immune alteration | Key findings in long COVID | References |
|---|---|---|
| T cell Dysfunction | Significant reduction in adaptive immune cells (T cells, particularly RTEs, and B cells) at 10 months post-infection. | () |
| Diminished CD8+ T cell response relative to CD4+ T cells at 6 months post-infection. | () | |
| PD-1+ SARS-CoV-2-specific CD8+ T cells may retain functionality. | () | |
| Memory B Cell Persistence | Persistent Spike IgG titers, stabilizing around 6 months post-infection. | () |
| Long-term persistence of SARS-CoV-2-specific memory B cells. | () | |
| Neutrophil Dysregulation & NETs | Persistently elevated serum NET markers (NE, MPO, cfDNA) for ≥6 months post-infection. | () |
| Upregulation of neutrophil activation signatures and inflammatory chemokines in airways >10 months post-infection. | () | |
| Elevated neutrophilic chemokines (CXCL8), inflammasome pathway components (NLRP3, IL-18/IL-18R1) correlating with persistent ILD. | () |
Immunological alterations in long COVID relevant to lung cancer microenvironment.
RTE, (Recent Thymic Emigrant); NETs, (Neutrophil Extracellular Traps); NE, (Neutrophil Elastase); MPO, (Myeloperoxidase); cfDNA, (Cell-free DNA); ILD, (Interstitial Lung Disease).
4.1 T cell exhaustion and dysfunction
T cells are central orchestrators of adaptive immunity, critical for maintaining health and combating disease. T cell development occurs in the thymus. Following antigen encounter in acute settings, naïve T cells differentiate into effector and memory subsets, which mediate direct killing, diversified immune regulatory functions and long-term protection. However, chronic antigen exposure, as seen in persistent viral infections and cancer, can drive T cells towards a state of functional exhaustion, characterized by progressive loss of effector function and sustained expression of inhibitory receptors like PD-1 and CTLA-4 (). This shared pathway of exhaustion underpins the conceptual overlap between immunotherapy strategies for chronic infections and cancer.
While much research focused on the acute phase of COVID-19, understanding the longitudinal immune trajectory in Long COVID is paramount. T cells are pivotal mediators of the host response to SARS-CoV-2. Longitudinal studies examined patients recovering from mild, moderate, and severe COVID-19 at two time points (3- and 6-months post-infection), focusing on the dynamic changes in T cell profiles post-infection. Overall, a trend towards exhaustion is observed, particularly in CD8+ T cells. Dysregulated immunity in CD4+, CD8+, and Treg subsets often persists for the first 3 months, with a partial functional shift becoming apparent between 3–6 months, the extent of which varies with initial infection severity. This manifests itself as long-lasting attenuated T cell activation, reduced proliferative capacity, and a shift towards an exhausted/senescent phenotype, particularly within the CD8+ compartment. Together with prolonged unresolved inflammation, this T cell dysfunctions likely contributes to compromised anti-tumor immunity (Wiech et al., 2022).
Paradoxically, some studies report that PD-1-expressing SARS-CoV-2-specific CD8+ T cells retain functionality rather than being fully exhausted (). This complexity suggests that severe outcomes in COVID-19, including Long COVID complications and potentially increased cancer susceptibility, may stem from a combination of SARS-CoV-2 infection, potential co-pathogens, and the resultant induction of immune cell dysfunction, prominently featuring T cell exhaustion ().
4.2 Persistence of SARS-CoV-2-specific memory B cells
B cells, originating from bone marrow hematopoietic stem cells, undergo maturation and selection before populating peripheral lymphoid organs (). Antigen-driven B cell responses involve classical germinal center (GC) reactions, leading to affinity maturation and long-lived plasma/memory cells, and extrafollicular (EF) responses (). While some infections/vaccines confer long-lasting, sometimes lifelong robust immunity, immunity against respiratory viruses like coronaviruses tend to be less durable (). In the “suppressed” immune microenvironment of chronic conditions, including Long COVID and cancer, activating B cells presents a potential therapeutic avenue. Analogous to chronic infections, tumor-infiltrating B lymphocytes (TIL-Bs) can exert anti-tumor effects via antibody production, T cell modulation, and direct cytotoxicity (Wang et al., 2019). It remains to be determined whether the specific memory B cells generated by the host in response to SARS-CoV-2 infection influence lung cancer progression or response to therapy, or whether strategies modulating these cells impact immunotherapy efficacy. Evidence from HPV-associated head and neck cancer suggests antigen-specific B cells may represent a novel approach for tumor immunotherapy (Wieland et al., 2021). Adaptive immunity to SARS-CoV-2, comprising antibodies, memory B cells, and T cells, protects against reinfection (). Serum antibody levels typically peak around 2–3 weeks post-infection and may wane over time (; ).
Among the majority of people, anti-SARS-CoV-2 serum antibodies persist for more than six months after the initial infection, but some patients lose their specific antibodies rapidly (; Zheng et al., 2021). Spike-specific IgG titers often persist for months, stabilizing at a protective plateau around 6 months and remaining detectable for at least 9 months in many convalescents (). Crucially, memory B cells exhibit remarkable longevity. They can persist for years, poised to rapidly differentiate into antibody-secreting plasma cells upon re-exposure (). Numerous studies confirm the persistence of SARS-CoV-2-specific memory B cells long after acute infection, making them a reliable correlate of durable humoral immunity (; ; Winklmeier et al., 2022). Consequently, quantifying these cells provides a robust indicator of long-term immune memory in Long COVID ().
4.3 Neutrophil extracellular traps and dysregulated neutrophil activity
Neutrophils, a subset of myeloid white blood cells, serve as primary responders to acute inflammatory and infection. In humans, neutrophils constitute 50-70% of the circulating leukocyte population (; ). As first responders, they combat pathogens via phagocytosis, degranulation, cytokine production, and the formation of neutrophil extracellular traps (NETs) – webs of DNA decorated with antimicrobial proteins (; ). During the initial phase of COVID-19 infection, neutrophils are recruited to the lungs where they eliminate the invading SARS-CoV-2 via multiple mechanisms. While essential for host defense, aberrant neutrophil activation is a hallmark of severe COVID-19, contributing to cytokine storms and exaggerated host immune responses in COVID-19 patients (). Persistent neutrophil infiltration signifies chronic inflammation and can drive tissue damage.
Within the tumor microenvironment (TME), neutrophils exhibit functional plasticity. They are often categorized as anti-tumor (N1 neutrophils) or pro-tumor (N2 neutrophils) phenotypes (). Tumor-derived factors, particularly the immunosuppressive cytokine TGF-β, promote polarization towards the pro-tumorigenic N2 state (). Neutrophil depletion studies in mice show modest anti-tumor effects, while TGF-β blockade via the TGF-β receptor inhibitor SM16 promotes accumulation of anti-tumor N1 neutrophils; subsequent neutrophil depletion under these conditions then accelerates tumor growth, highlighting their context-dependent role (). Additionally, type I interferons appear involved in inducing N1 polarization post-TGF-β inhibition (). In chronic inflammation, distinct neutrophil subsets recruit different immune infiltrates, exerting divergent effects on tumors. This evidence suggests that targeting neutrophils polarization or NETosis thus represents a promising therapeutic strategy for both COVID-19 sequelae and lung cancer.
Substantial evidence indicates dysregulated neutrophil activity in Long COVID. Circulating neutrophils from Long COVID patients demonstrate heightened NET formation (; ; Woodruff et al., 2023). Longitudinal monitoring of NET markers (serum neutrophil elastase (NE), myeloperoxidase (MPO), cell-free DNA) in previously hospitalized patients shows levels remain significantly elevated for at least 6 months post-infection compared to controls, albeit lower than during acute infection (). In the context of Long COVID, compared to age and gender-matched healthy controls, survivors also exhibit significantly higher levels of detectable antinuclear antibodies at both 3- and 12-months post-infection (). Patients with persistent post-COVID interstitial lung abnormalities show elevated neutrophil counts and serum MPO, correlating with radiological disease extent. Proteomic analysis identifies the neutrophil chemotactic factor IL-17 and neutrophil chemokines (CXCL1, CXCL8) as significantly associated with persistent lung disease and functional impairment (). Furthermore, single-cell transcriptomic analysis of airways in Long COVID patients (>10 months post-acute infection) reveals increased neutrophil abundance and upregulated neutrophil activation signatures alongside inflammatory chemokines across multiple cell clusters, pointing to sustained neutrophilic inflammation ().
5 Lung cancer immunotherapy in the context of COVID-19 vaccination
Immune checkpoints (ICs) like PD-1, CTLA-4, and TIM-3, expressed on various immune cells (T cells, NK cells, DCs), deliver inhibitory signals that suppress immune activation. In chronic conditions like cancer and persistent infections, sustained IC/ligand expression drives T cell exhaustion, enabling antigen-mediated immune escape. ICIs, which block these pathways, have demonstrated significant efficacy in treating various cancers (; Wykes and Lewin, 2018). Although many studies have revealed that ICI immunotherapy holds promising clinical prospects in patients with infectious diseases (), key questions arise regarding their interaction with SARS-CoV-2 infection and vaccination in lung cancer patients: Does ICI reduce SARS-CoV-2 viral load? Should ICI regimens be adjusted upon SARS-CoV-2 infection? This section focuses on the potential interactions between ICI therapy for lung cancer and COVID-19 vaccination.
5.1 Safety of ICI during the COVID-19 pandemic: a nuanced picture
The association between ICI treatment for lung cancer and COVID-19 severity remain debated. Some studies suggest older age and ICI treatment correlate with worse COVID-19 outcomes (; Zhou et al., 2020). Conversely, other studies including larger cohorts, report no significant association between ICI monotherapy and increased COVID-19 severity or mortality (; ). Most evidence indicates that ICI immunotherapy alone is not strongly associated with heightened COVID-19 severity. A clinical study of 69 lung cancer patients with COVID-19 (41 previously treated with PD-1 blockade, 28 untreated) found no difference in COVID-19 severity between groups (). Furthermore, a large multicenter observational study (TERAVOLT) indicated that various systemic anti-cancer therapies (including pembrolizumab, nivolumab, ipilimumab, ICI-chemotherapy combinations, TKIs, chemotherapy alone) did not significantly affect the survival rate in lung cancer patients with COVID-19 ().
However, an important caveat emerges regarding combination ICI therapy. Lung cancer patients treated with dual immunotherapy (e.g., nivolumab + ipilimumab) may face a higher risk of severe complications or death if infected with SARS-CoV-2. A 70-year-old patient diagnosed with COVID-19 and lung adenocarcinoma received the dual immunotherapy (nivolumab and ipilimumab) but died from cytokine release syndrome (). Additionally, clinical cases report fatalities due to cytokine release syndrome (CRS) in such patients, and registry data indicate significantly higher mortality rates associated with combination ICI compared to monotherapy ().
Intriguingly, emerging data suggest potential immunostimulatory effects. Compared to the general population, NSCLC patients receiving pembrolizumab combined with chemotherapy exhibited stronger humoral immune responses to SARS-CoV-2 infection (higher SARS-CoV-2 reactive IgG, neutralizing antibodies) and enhanced cellular immunity (sustained increases in follicular helper T cells, activated CD4+ and CD8+ T cells) (). This hints at a potential “mutually beneficial” interaction between certain anti-cancer immunotherapies and anti-viral immunity.
5.2 Exploring a “mutually beneficial” interaction
Clinical observations suggest that cancer patients receiving ICI may have a lower risk of SARS-CoV-2 infection or experience milder COVID-19 symptoms (). The mechanistic basis for this phenomenon likely relates to the restoration of T cell function by ICI. Preclinical evidence indicates that anti-PD-1 therapy can reinvigorate exhausted antiviral T cell responses, reducing viral load (). Supporting this, clinical cases describe lung cancer patients receiving ICI who contracted COVID-19 did not exhibit obvious signs of pulmonary involvement (Yang and Xu, 2023).
Conversely, COVID-19 vaccination may enhance the efficacy of ICI in cancer treatment. Global vaccination efforts have deployed various platforms, including mRNA-based vaccines and adenovirus vector vaccines expressing the SARS-CoV-2 spike protein (CoV-2-S). Specifically, nucleoside-modified mRNA encoding antigens encapsulated in LNP (mRNA-LNP) have shown great promise and been widely accepted, demonstrating an efficacy of approximately 95% in healthy subjects (; ). Recent research explores vaccines designed to elicit robust CD8+ cytotoxic T lymphocyte (CTL) responses against SARS-CoV-2, particularly relevant for high-risk groups like cancer patients. Preclinical studies demonstrate that vaccines inducing lung-homing T cells or dual-antigen vaccines targeting both tumor-associated antigens (TAAs) and SARS-CoV-2 can generate potent anti-tumor effects alongside virus-specific CTLs ().
Critically, clinical retrospective evidence supports this synergy. A retrospective study analyzed the survival data of 104 stage III-IV NSCLC patients treated with ICI. Compared with the unvaccinated group, the Overall Response Rate (ORR: 28.0% vs. 11.39%, p = 0.05) was significantly improved in the COVID-19 vaccinated group. Regarding long-term survival benefits, the COVID-19 vaccine had a profound impact on the progression free survival (PFS: HR = 0.16, p = 0.021) and overall survival (OS: HR = 0.168, p = 0.019) of NSCLC patients treated with ICI. Compared with the unvaccinated group, Both PFS (p < 0.001) and OS (p < 0.001) were significantly prolonged in the vaccinated group. Furthermore, vaccinated patients exhibited higher circulating CD4+ T cell levels (p = 0.047). This study strongly suggests that COVID-19 vaccination enhances the efficacy of anti-PD-1 immunotherapy in advanced NSCLC, potentially offering additional survival benefits for these NSCLC patients ().
6 Discussion and conclusion
This review underscores the critical need to understand the impact of Long COVID on the host immune system, particularly concerning lung cancer pathogenesis and immunotherapy efficacy. Long COVID, characterized by persistent symptoms and profound immune alterations-including T cell exhaustion, dysregulated neutrophil activity, and persistent but altered B cell memory-can significantly reshape the tumor immune microenvironment. These changes hold substantial implications for the effectiveness of immunotherapies like ICI, which are crucial for lung cancer treatment.
We have outlined the potential mechanisms by which Long COVID may contribute to lung cancer development, encompassing post-infection pulmonary fibrosis, chronic inflammation, cytokine imbalance, and dysregulation of the RAAS. Furthermore, we explored how Long COVID-associated immunopathology, notably involving dysfunctional T cells, persistent memory B cells, and neutrophil extracellular traps, may remodel the lung cancer microenvironment. The evolving landscape also reveals complex interactions between lung cancer immunotherapy and COVID-19 vaccination. While the safety of ICI monotherapy during the pandemic appears generally acceptable, caution is warranted with combination ICI regimens. Importantly, emerging clinical evidence points towards a potential “mutually beneficial” relationship, where ICI might modulate anti-viral responses and COVID-19 vaccination could enhance ICI efficacy in lung cancer patients, significantly improving survival outcomes.
In conclusion, the immunologic perturbations and tissue remodeling associated with Long COVID present distinct challenges for lung cancer patients undergoing immunotherapy. Moving forward, research efforts should prioritize:
Investigating the Molecular Mechanisms: Elucidating the specific molecular mechanisms by which Long COVID-related immune dysregulation (e.g., persistent cytokine signaling, altered T cell receptor repertoire) promotes lung cancer development and progression. This includes identifying novel therapeutic targets to interrupt these pathways.
Conducting Longitudinal Studies: Implementing large-scale longitudinal studies to assess the long-term cancer risk in Long COVID patients, with comprehensive immune profiling and clinical follow-up.
Developing Targeted Therapeutic Strategies: Designing and testing targeted therapeutic strategies to mitigate the pro-tumorigenic effects of Long COVID, such as combining anti-inflammatory agents with immunotherapies or developing novel interventions to restore T cell function and reverse fibrosis.
Applying Multi-omics Approaches: Utilizing multi-omics approaches (genomics, proteomics, metabolomics) to identify predictive biomarkers for cancer risk and immunotherapy response in Long COVID patients.
Statements
Author contributions
SZ: Writing – review & editing, Supervision. XL: Writing – original draft. LJ: Writing – original draft. WC: Writing – review & editing. YX: Writing – review & editing. HD: Writing – review & editing.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. The financial support was granted by the “Lvyangjinfeng” Program of Yangzhou City (YZLYJFJH2023YXBS180, SZ).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Abbreviations
ICI, immune checkpoint inhibitors; SARS-CoV-2, syndrome coronavirus 2; ACE2, angiotensin-converting enzyme 2; PACS, post-acute COVID syndrome; PD-1, programmed death 1; CTLA-4, cytotoxic T lymphocyte antigen-4; NSCLC, non-small cell lung cancer; Ang-II, Angiotensin II; GC, germinal center; EF, extrafollicular; NETs, neutrophil extracellular traps; NE, neutrophil elastase; MPO, myeloperoxidase; ICs, Immune checkpoints; OS, overall survival,
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Summary
Keywords
long covid, lung cancer, t-cell exhaustion, immune checkpoint inhibitors, pulmonary fibrosis, COVID-19 vaccination
Citation
Lv X, Ji L, Cao W, Xue Y, Dai H and Zhang S (2025) Revisiting lung cancer immunotherapy in the era of long COVID: mechanistic insights and therapeutic implications. Front. Cell. Infect. Microbiol. 15:1657691. doi: 10.3389/fcimb.2025.1657691
Received
01 July 2025
Accepted
20 October 2025
Published
04 November 2025
Volume
15 - 2025
Edited by
Jing Yang, Tongji University, China
Reviewed by
Caishang Zheng, University of Texas MD Anderson Cancer Center, United States
Gian Marco Leone, University of Catania, Italy
Updates
Copyright
© 2025 Lv, Ji, Cao, Xue, Dai and Zhang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shengzhe Zhang, zhangshengzhe@yzu.edu.cn
†These authors have contributed equally to this work
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