Jakobsen KK, Rehman U, Grønhøj C
… +4 more, Lau ZJ, Klussmann JP, Lechner M, von Buchwald C
Int J Cancer
· 2026 Aug · PMID 41947334
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Human papillomavirus (HPV) is one of the primary causes of oropharyngeal squamous cell carcinoma (OPSCC), accounting for around 70% of cases in high-income countries. In Denmark, OPSCC is the most common head and neck ca...Human papillomavirus (HPV) is one of the primary causes of oropharyngeal squamous cell carcinoma (OPSCC), accounting for around 70% of cases in high-income countries. In Denmark, OPSCC is the most common head and neck cancer, yet public awareness of HPV's role has not been assessed in Denmark. This study aims to assess HPV awareness and estimate the future disease and economic burden of OPSCC in Denmark. A nationally representative cross-sectional survey of 559 Danish adults was conducted in January 2025 to evaluate awareness of HPV, its link to OPSCC, and perceptions of vaccination. Age-adjusted incidence rates were calculated from the Danish Cancer Registry (1980-2021) and projected to 2039 and used to estimate the economic burden from treatment costs and productivity losses. Between 1980 and 2021, the incidence of OPSCC increased 7.3-fold in Denmark. Projections indicate that by 2039, the incidence among men will reach 12.3 cases (95% CI 11.7-12.8) per 100,000 population. The cumulative economic burden of OPSCC from 2025 to 2039 is estimated at €2.23 billion (95% CI 2.12-2.33), with productivity losses accounting for the majority of costs. Despite the prevalence and economic impact, public awareness of HPV and its association with OPSCC remains limited in Denmark. Among survey respondents, 38.5% had never heard of HPV, and only 37.0% recognized its link to OPSCC. These findings underscore the urgent need for comprehensive public education, awareness initiatives, and strengthened early detection initiatives to curb the rising incidence and substantial economic impact of HPV-associated OPSCC in Denmark.
Hirabayashi M, Georges D, Combes JD
… +1 more, Clifford GM
Int J Cancer
· 2026 Aug · PMID 41947331
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There is evidence for a causal role of Epstein-Barr virus (EBV), a known carcinogen, in an increasing number of lymphoma subtypes, but a systematic evaluation of EBV attributable fraction is lacking. We conducted a syste...There is evidence for a causal role of Epstein-Barr virus (EBV), a known carcinogen, in an increasing number of lymphoma subtypes, but a systematic evaluation of EBV attributable fraction is lacking. We conducted a systematic review and meta-analysis of EBV prevalence in lymphoma subtypes from 1990 to 2024, stratified by HIV status and geographical region. For each subtype, we calculated pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV, measured by EBV-encoded RNA in situ hybridisation. 307 eligible studies, including > 21,140 lymphoma cases, were included. In HIV-negative persons, EBV pooled prevalence was 10.8% (95% CI 8.6%-13.5%) in Diffuse large B-cell lymphoma (DLBCL), 45.8% (35.2%-56.8%) in Burkitt lymphoma (BL), 53.0% (46.9%-58.9%) in Hodgkin lymphoma, 52.5% (29.6%-74.4%) in plasmablastic lymphoma, 92.4% (83.3%-96.7%) in extranodal NK/T-cell lymphoma (ENKTL), and 5.1% (2.7%-9.4%) in follicular lymphoma. EBV prevalence was higher among tumors diagnosed among persons living with HIV (PLHIV), for DLBCL (43.6% (95% CI 31.5%-56.5%)), BL (43.3% (27.9%-60.2%)), and PBL (79.4% (65.6%-88.6%)), compared to HIV-negative tumors. BL was the only subtype with evidence of heterogeneity in EBV positivity by region, with near-universal EBV positivity in East African BL. This provides the first systematic and comprehensive evidence on EBV's substantial contribution to lymphoma, highlighting its particular importance in lymphomas arising in PLHIV. These data can contribute to estimating the complete burden of EBV-related disease and inform public health and clinical strategies, including vaccines, early diagnosis, or targeted therapies.
Matas I, Torné A, Saco A
… +11 more, Martí C, Cardiel A, Rakislova N, Marimon L, Glickman A, Victoria I, Alós S, Lopez-Diaz J, Fusté P, Ordi J, Del Pino M
Int J Cancer
· 2026 Aug · PMID 41944777
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The incidence of anal squamous cell carcinoma (ASCC) is rising, and women with genital human papillomavirus (HPV) infection or HPV-associated high-grade squamous intraepithelial lesions (HSIL) are at high risk of develop...The incidence of anal squamous cell carcinoma (ASCC) is rising, and women with genital human papillomavirus (HPV) infection or HPV-associated high-grade squamous intraepithelial lesions (HSIL) are at high risk of developing ASCC. We conducted a cross-sectional study including 354 immunocompetent women referred for anal evaluation because of HPV infection or HSIL of the lower genital tract between 2019 and 2024. Participants were categorized according to the genital site affected by HSIL (uterine cervix, vagina, vulva/perineum/perianal region, or multicentric disease), and a control group of 99 immunocompetent women with genital HPV infection and/or low-grade SIL was included. All patients underwent anal high-risk HPV testing, liquid-based cytology, and high-resolution anoscopy when indicated. Overall, high-risk HPV infection and HSIL were identified in the anal canal in 62.5% and 5.6% of women, respectively. Women with multicentric disease showed a higher prevalence of anal HSIL compared with the control group (6/29, 20.7%, vs. 2/99, 2.0%; p = .031), and the other genital HSIL groups (11/182, 6.0% for cervical; 0/13, 0%, for vaginal; 1/31, 3.2% for vulvar HSIL; p = .003). Genital HSIL, particularly multicentric disease, was a strong marker of anal involvement. No HSIL/AIN occurred among women with a negative anal high-risk HPV test. Anal high-risk HPV testing alone showed optimal sensitivity (100%) and negative predictive value (100%) for the diagnosis of HSIL/AIN, whereas cytology alone had lower sensitivity (68.4%). Combining both tests did not improve accuracy and resulted in excessive referrals. High-risk HPV testing alone appears to be the most efficient approach for anal screening in women with genital HSIL.
Zohar K, Strecker M, Wartmann T
… +14 more, Shi W, Stelter F, Doelling M, Andric M, Kakhlon O, Täger C, Schanze D, Linnebacher M, Naumann M, Stange DE, Jechorek D, Croner RS, Linial M, Kahlert UD
Int J Cancer
· 2026 Aug · PMID 41922912
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Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, underscoring the urgent need for precise and personalized therapeutic strategies. Globo-H has emerged as a clinically relevant glycan target...Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, underscoring the urgent need for precise and personalized therapeutic strategies. Globo-H has emerged as a clinically relevant glycan target with promising diagnostic and therapeutic utility across multiple cancer types. In this study, we stratified colorectal cancer patients into Globo-H-high and Globo-H-low groups using a histology-based classification, followed by RNA-sequencing analyses to elucidate the key signaling pathways associated with Globo-H overactivation. Among the 31 genes that were identified to meet the Globo-H histology criterion, DUSP14 (dual specificity phosphatase 14) emerged as a promising pharmacological target associated with Globo-H abundance. DUSP14 is an underexplored but pharmacologically actionable therapeutic target. DUSP14 protein in colon cancer cells is inversely correlated with total Transforming growth factor-β-activated kinase 1 (TAK1) protein. The druggability of DUSP14 was demonstrated through in vitro using cell lines and patient-derived organoids (PDO). These results enhance current diagnostic frameworks and provide a foundation for developing novel targeted therapies. Further, in vivo studies are warranted to evaluate the potential of Globo-H targeting in combination with standard treatment regimens. Overall, our work highlights the value of integrating PDO-based functional assays with molecular profiling to uncover and validate actionable targets for CRC theranostics.
Int J Cancer
· 2026 Aug · PMID 41918327
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M. Lourda, I. P. Trougakos and E. S. Gonos, "Development of Resistance to Chemotherapeutic Drugs in Human Osteosarcoma Cell Lines Largely Depends on Up-Regulation of Clusterin/Apolipoprotein J," International Journal of...M. Lourda, I. P. Trougakos and E. S. Gonos, "Development of Resistance to Chemotherapeutic Drugs in Human Osteosarcoma Cell Lines Largely Depends on Up-Regulation of Clusterin/Apolipoprotein J," International Journal of Cancer 120, no. 3 (2007): 611-622, https://doi.org/10.1002/ijc.22327. The above article, published online on 09 November 2006 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Christoph Plass; the Union for International Cancer Control; and John Wiley & Sons, Ltd. The retraction has been agreed upon following concerns raised by a third party. An investigation identified a duplication between the R2 and R3 PARP bands shown in Figure 2D. A further duplication was found between the R2, Sc-I, PARP band in Figure 7A and the R2, Cl-I PARP band in Figure 7B; these bands represent different cell lines. The authors cooperated with the investigation, but due to the time that has elapsed since publication, they were unable to provide any original data. The editors consider the results and conclusions to be unreliable. The authors disagree with the retraction.
Meneses-León J, Rivera-Paredez B, Hernández-Salazar S
… +9 more, Torres-Ibarra L, Carnalla M, León-Maldonado L, Hernández-López R, Cadena-Fiscal JD, Moscicki AB, Quiterio-Trenado M, Lazcano-Ponce E, Salmerón J
Int J Cancer
· 2026 Aug · PMID 41902757
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Extended high-risk human papilloma virus (hrHPV) typing emerges as a potential alternative for detecting cervical intraepithelial neoplasia 3 (CIN3), without additional triage tests. We evaluate the extended hrHPV typing...Extended high-risk human papilloma virus (hrHPV) typing emerges as a potential alternative for detecting cervical intraepithelial neoplasia 3 (CIN3), without additional triage tests. We evaluate the extended hrHPV typing as an alternative to improve CIN3 detection within an HPV-based screening program. Between January 2017 and August 2018, 5856 women aged 25-65 years were screened as part of a public cervical cancer screening program of the Tlalpan Sanitary Jurisdiction in Mexico City. HPV testing was performed by BD Onclarity™, which individually detects hrHPV types 16, 18, 31, 45, 51, and 52, and pools of types 33/58, 56/59/66, and 35/39/68. Specific hrHPV types within these pools were further identified using the Atila AmpFire platform. All HPV-positive women (n = 691) were referred to colposcopy evaluation for diagnostic confirmation. Of these, 561 women completed both colposcopy and histological confirmation, representing our analytical sample. HPV-16 alone had a sensitivity of 43.0% and specificity of 85.4% for CIN3 detection. Sequentially adding HPV-18/33/31/39 increased sensitivity to 100% for CIN3 detection, although with lower specificity (54.5%). The proportion of HPV-16/18/33/31/39 positive women was 47.0%, with a CIN3 PPV 5.3%. Extended genotyping with HPV-16/18/33/31/39 achieved 100% sensitivity for CIN3 detection, but a moderate specificity. This strategy aligns with the international recommendation for colposcopy referral in women with a PPV of CIN3 larger than 4.0%.
Wang Q, Zhou S, Fang X
… +3 more, He X, Wang G, Wang N
Int J Cancer
· 2026 Jul · PMID 41902313
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Gastric signet ring cell carcinoma (GSRCC) is a special type of gastric cancer common in young women. Diffuse gastric cancer (DGC) begins with intramucosal lesions comprising differentiated GSRCC cells. Genetically, GSRC...Gastric signet ring cell carcinoma (GSRCC) is a special type of gastric cancer common in young women. Diffuse gastric cancer (DGC) begins with intramucosal lesions comprising differentiated GSRCC cells. Genetically, GSRCC and DGC are clonally identical, with their morphology influenced by extracellular Wnt signaling. Interestingly, Wnt activation facilitates the transition of indolent GSRCC cells into more invasive DGC cells, indicating the high plasticity of GSRCC cells. With respect to its cellular origin, GSRCC may originate from MUC5AC-/MUC6- pre-pit cells in the proliferative area of the gastric gland. Importantly, the tumor immune microenvironment (TIM) of GSRCC has unique characteristics. Compared with that of non-GSRCC, the TIM of GSRCC seems to be in a relatively "quiescent" state, and CD4 and CD8 T cells are difficult to activate. Moreover, compared with non-GSRCC patients, GSRCC patients have significantly greater Treg infiltration and significantly fewer CD8 T effector cells. This immune "quiescent" state may explain the poor response to immunotherapy in patients with GSRCC. Notably, the depletion of CXCL13 derived from exhausted CD8 T cells (CD8-Tex) and the absence of mature tertiary lymphoid structures are key reasons for the low response to immunotherapy in patients with GSRCC. Therefore, for patients with GSRCC, enhancing the ability of CD8-Tex cells to produce CXCL13 may be the key to improving the immune therapy response. In this review, we explore recent key findings on GSRCC, focusing on molecular mechanisms, immune regulation, and prospective research directions to improve clinical applications.
Liu D, Xu B, Huang D
… +6 more, Sun Z, Zhu T, Hu P, Jiao D, Zhang F, Lin L
Int J Cancer
· 2026 Aug · PMID 41882494
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Patients with liver metastases generally have poorer outcomes following immunotherapy compared with those without liver involvement, and whether local ablation can enhance systemic antitumor immunity remains unclear. In...Patients with liver metastases generally have poorer outcomes following immunotherapy compared with those without liver involvement, and whether local ablation can enhance systemic antitumor immunity remains unclear. In this retrospective study, we evaluated the efficacy of combining ablation with PD-1 inhibitor therapy versus PD-1 inhibitor monotherapy in patients with liver metastases. A total of 1337 patients who received PD-1 inhibitors with or without ablation between January 2017 and September 2022 at three institutions were reviewed. After propensity score matching, 234 patients were included, with 117 in the combination group and 117 in the monotherapy group. The combination group achieved significantly longer median overall survival (20.13 vs. 13.83 months, p = .023) and progression-free survival (12.73 vs. 5.20 months, p < .001). Progression of extrahepatic lesions was markedly lower in the combination group than in the monotherapy group (35.9% vs. 66.7%, p < .001). Treatment-related adverse events were common in both groups, with a higher frequency of grade 1-2 events such as transaminase elevation, fever, nausea, vomiting, and abdominal pain in the combination group, while the incidence of grade 3-4 toxicities was comparable between groups and no treatment-related deaths occurred. Multivariate Cox regression confirmed treatment modality as an independent prognostic factor for survival (p < .001). These findings suggest that ablation of intrahepatic lesions may alleviate systemic immunosuppression and augment the efficacy of immunotherapy. The combination of ablation and PD-1 inhibitors represents a promising therapeutic approach for patients with liver metastases.
Tian J, Zhang X, Sun X
… +5 more, Liu W, Long L, Zang J, Chen J, Xiao J
Int J Cancer
· 2026 Jul · PMID 41874196
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The mechanism by which membrane-expressed programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, mediates tumor immune evasion is well established. Recent studies, however, have revealed that PD-L1 can unde...The mechanism by which membrane-expressed programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, mediates tumor immune evasion is well established. Recent studies, however, have revealed that PD-L1 can undergo nuclear translocation (nuclear PD-L1, nPD-L1) and contribute to tumor progression through nonimmune-dependent mechanisms. Nuclear translocation of PD-L1 involves p300-mediated acetylation, Huntingtin-interacting protein 1-related protein-dependent endocytosis, and Vimentin-importin α/β pathway-mediated nuclear transport, and is dynamically regulated by histone deacetylase 2-mediated deacetylation. Once localized in the nucleus, PD-L1 promotes angiogenesis and immune evasion by regulating target genes such as early growth response 1. It also participates in nonimmune functions, including DNA damage repair, sister chromatid cohesion, and pyroptosis, exhibiting both pro-tumorigenic and potential tumor-suppressive roles. Moreover, regulation of PD-L1 subcellular localization via MIB2-mediated ubiquitination and small-molecule inhibitors such as BMS1166 offers new insights for targeted therapy. This review systematically summarizes the molecular mechanisms underlying PD-L1 nuclear translocation, its biological functions, roles within the tumor microenvironment, and potential as a biomarker and therapeutic target. Emphasis is placed on addressing functional heterogeneity and mitigating experimental artifacts, which is critical for translational research.
Liu Y, Li B, Wang Z
… +8 more, Zheng S, Zhang X, Qiu X, Jiang Z, Dong T, Jiang C, Du C, Wang L
Int J Cancer
· 2026 Aug · PMID 41872730
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Immune checkpoint inhibitor (ICI)-based therapy is standard care for advanced or recurrent esophageal squamous cell carcinoma after radical treatment, yet the effect of prior lymphatic interventions on ICI efficacy remai...Immune checkpoint inhibitor (ICI)-based therapy is standard care for advanced or recurrent esophageal squamous cell carcinoma after radical treatment, yet the effect of prior lymphatic interventions on ICI efficacy remains unclear. Because tumor-draining lymph nodes serve as key hubs of anti-tumor immunity, this study evaluated how prior lymphadenectomy or nodal irradiation influences subsequent ICI outcomes. We retrospectively analyzed 507 patients, including 302 with recurrent esophageal squamous cell carcinoma after surgery or radiotherapy and 205 with treatment-naïve advanced disease, all treated with ICI-based regimens. In the postoperative recurrence group, an optimal lymph node yield range emerged. Patients with 16-22 dissected lymph nodes (DLNs) achieved significantly longer progression-free survival (PFS; 12.20 months) than those with ≤16 DLNs (7.17 months) or >22 DLNs (6.37 months). DLN group remained an independent prognostic factor for PFS in multivariate analysis. Among patients with post-radiotherapy recurrence, prior involved-field irradiation correlated with significantly longer PFS than elective nodal irradiation (8.30 vs. 5.10 months). These findings suggest an association between prior lymphatic intervention and PFS in patients receiving immunotherapy. A moderate extent of lymphadenectomy and the use of IFI were associated with improved PFS. These results underscore the importance of carefully balancing locoregional disease management with preservation of lymphatic immune architecture in the immunotherapy era.
Du F, George TJ, Guo Y
… +9 more, Khosrow-Khavar F, Liu Q, Perkins CM, Jiang J, DeRemer DL, McDonough C, Lian Y, Schmittgen TD, Jiao T
Int J Cancer
· 2026 Aug · PMID 41872700
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Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality worldwide. Preclinical studies suggest that the renin-angiotensin-aldosterone system (RAAS) inhibitors may help prevent PDAC by promoti...Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality worldwide. Preclinical studies suggest that the renin-angiotensin-aldosterone system (RAAS) inhibitors may help prevent PDAC by promoting acinar ductal metaplasia reversal, as the RAAS pathway is most inhibited during this process. Our study aims to examine the association between RAAS inhibitor use and the risk of PDAC compared with calcium channel blockers (CCB). Leveraging the target trial emulation framework, we used US Medicare data to emulate a new user, active comparator trial examining the effects of initiating RAAS inhibitors (exposure group) versus CCB (control group), with randomization emulated by propensity score matching with 2:1 ratio. Eligible patients were aged >65 years without malignant cancer or palliative care. Outcomes included PDAC and all-cause mortality. Cox proportional hazards models with inverse probability censoring weight were applied. After propensity score matching, our study included 214,262 patients who initiated RAAS inhibitors and 107,131 patients who initiated CCB, with mean ages of 76.5 and 77.0 years, respectively, and a similar proportion of women (60.9% vs. 61.8%) between two groups. During follow-up, the incidence of PDAC was significantly lower in the RAAS inhibitor group than in the CCB group, corresponding to a 46% reduction in PDAC risk (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.49-0.59). Similarly, all-cause mortality was 22% lower among RAAS inhibitors users compared with CCB users (HR: 0.78, 95% CI: 0.77-0.79). These findings warrant further investigation into RAAS inhibitors' potential benefits, including identification of confounding factors like genetics and biomarkers.
Fan X, Wei C, Rong M
… +5 more, Wang S, Wang J, Wang X, Han X, Meng X
Int J Cancer
· 2026 Jul · PMID 41872688
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PD-L1 is a reliable biomarker for predicting immunotherapy efficacy in NSCLC patients without driver gene mutations. However, its significance in patients with driver gene-positive tumors remains unclear. This study anal...PD-L1 is a reliable biomarker for predicting immunotherapy efficacy in NSCLC patients without driver gene mutations. However, its significance in patients with driver gene-positive tumors remains unclear. This study analyzed 273 patients with stage IV non-small cell lung cancer harboring driver gene mutations. All patients had PD-L1 expression levels ≥10%. The effect of PD-L1 expression on progression-free survival (PFS) and overall survival (OS) was assessed. Among the 273 patients with driver gene-positive NSCLC, 127 had a PD-L1 tumor proportion score (TPS) of 10-49%, and 146 had TPS ≥50%. Patients in the TPS 10%-49% group had significantly better median PFS and OS compared to those in the TPS ≥50% group (p = 0.0008 and p = 0.0009, respectively). In the realm of targeted therapy, patients who received first-line tyrosine kinase inhibitors (TKIs) showed superior outcomes in the TPS 10-49% group compared to the TPS ≥50% group in terms of both median PFS (30.8 months vs. 13.9 months, p = .0001) and OS (44.8 months vs. 26.3 months, p = .0006). Regarding immunotherapy, PD-L1 expression level was not significantly associated with treatment efficacy. However, in patients with KRAS mutations, those who received first-line immunotherapy exhibited better median PFS and OS (p <.0001 for both). Notably, among patients with high PD-L1 expression, no statistically significant clinical benefit was observed. In NSCLC patients with driver gene mutations, PD-L1 expression is associated with the efficacy of targeted therapy but is not predictive of response to immunotherapy.
Acker F, Wenger K, Reck M
… +17 more, Waller CF, Hoffknecht P, Bethge A, Nusch A, Reiser M, Bernhardt C, Bendel M, Lennartz C, Fleitz A, Jänicke M, Ludwig P, Groth A, Griesinger F, Thomas M, Eberhardt WEE, Sebastian M, CRISP Registry Group
Int J Cancer
· 2026 Aug · PMID 41872110
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Brain metastases (BM) from non-small cell lung cancer (NSCLC) are a relevant cause of morbidity and mortality. This study aims to identify a population at high risk for BM in order to inform personalized follow-up strate...Brain metastases (BM) from non-small cell lung cancer (NSCLC) are a relevant cause of morbidity and mortality. This study aims to identify a population at high risk for BM in order to inform personalized follow-up strategies in the future. We have therefore developed and validated a point-based risk classifier for the risk of BM1 in patients with metastatic non-oncogene-addicted NSCLC without BM at disease onset. A total of 3139 patients were included from the German CRISP lung cancer registry and randomly assigned to a derivation and validation set (2:1). In the derivation set, a Fine and Gray model was developed considering BM and death competing risks. A point-based risk classifier was derived and evaluated in the validation set. Of the baseline variables included in the risk model, ≥4 versus 0 extrathoracic metastatic sites (hazard ratio [HR], 2.69; 95% CI, 1.45-5.00), N3 vs. N0 disease (2.29; 1.41-3.72), and age < 65 vs. ≥75 years (2.03; 1.39-2.98) were the strongest predictors of BM development. Using the risk classifier, high-risk patients in the derivation set had a cumulative incidence of BM of 23.7% (95% CI, 16.7-30.1) at 18 months compared to 10.3% (8.9-11.7) in low-risk patients (HR, 2.44; 95% CI, 1.87-3.19). In the validation set, the cumulative incidence of BM at 18 months was 14.7% (11.5-17.8) and 8.9% (6.2-11.6) in the high-risk and low-risk groups, respectively (HR, 1.54; 95% CI, 1.08-2.20). In conclusion, our point-based risk classifier is able to identify NSCLC patients at high risk for BM development that may benefit from intensified brain surveillance.
Tang W, Hou X, Li L
… +11 more, Zhao H, Tang X, Zhu W, Yan X, Liu J, Wu Q, Qiao Z, Hu S, Zhang M, Li X, Xie P
Int J Cancer
· 2026 Aug · PMID 41863042
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Coronavirus disease 2019 (COVID-19) remains a global health threat, particularly for patients with cancer, who experience greater susceptibility and worse outcomes. Epidermal growth factor receptor (EGFR)-tyrosine kinase...Coronavirus disease 2019 (COVID-19) remains a global health threat, particularly for patients with cancer, who experience greater susceptibility and worse outcomes. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is standard first-line therapy for advanced EGFR-mutated non-small cell lung carcinoma (NSCLC). However, the impact of COVID-19 on TKI efficacy remains unclear. This multicenter retrospective study included patients with stage IV EGFR-mutated NSCLC who received first-line EGFR-TKI treatment at four Chinese hospitals. Leveraging China's policy change (December 2022), we compared a pre-pandemic COVID-19-negative cohort (January 2019-November 2022) with a COVID-19-positive cohort (January-June 2023). After 1:1 propensity score matching (PSM), Kaplan-Meier and Cox regression analyses evaluated progression-free survival (PFS) and prognostic factors. Among 711 patients (median follow-up, 37.90 months), the COVID-19-negative group had significantly longer median PFS (18.17 vs. 12.89 months; p = .001). After PSM, we analyzed 426 well-matched patients (213/cohort). Before and after matching, COVID-19-negative patients exhibited better PFS with all EGFR-TKI generations (unmatched: p <.001, p = .030, and p = .001; matched: p <.001, p = .049, and p = .015). COVID-19 infection worsened outcomes in both monotherapy and combination therapy. Multivariable analysis identified COVID-19 infection as an independent predictor of worse PFS (hazard ratio 1.650, 95% confidence interval: 1.286-2.116; p < .001). Adenocarcinoma, ≤3 metastatic organs, smoking index >570, concurrent systemic therapy, and third-generation TKI were also prognostic. COVID-19 infection markedly reduces EGFR-TKI efficacy in patients with advanced NSCLC, warranting closer monitoring during and after infection and supporting adaptive management strategies.