Efficacy and safety of immune checkpoint inhibitors in EGFR-mutant NSCLC patients with EGFR-TKI resistance: an updated systematic review and meta-analysis

Introduction

In 2022, lung cancer ranked first in the world in terms of the global incidence and mortality rates (1). Non-small cell lung cancer (NSCLC) is the main pathological type, comprising approximately 80–85% of all lung cancers, with most patients showing advanced or metastatic disease when first diagnosed (2). The PIONEER prospective study was the first to demonstrate a higher epidermal growth factor receptor (EGFR) mutation frequency (51.4% overall) in Asian patients with lung adenocarcinoma than that in Caucasian populations (approximately 20%), especially in non-smoking women (3). EGFR-tyrosine kinase inhibitors (TKIs) are the first-line therapy for patients with advanced NSCLC with EGFR mutations, but their efficacy is ultimately limited by the development of resistance. The T790M mutation, targeted by third-generation TKIs, was the main failure mode of first- and second-generation TKIs. Similarly, third-generation TKIs also exhibit the problem of resistance (4). Other known resistance mechanisms include EGFR-dependent C797X, G796, BRAF, human epidermal receptor (HER)2 amplification, and gene fusion or chromosomal rearrangements. In addition, it may transform from lung adenocarcinoma to small-cell lung cancer while preserving EGFR mutations (5). Moreover, C797S mutation, MET/HER2 amplification, bypass gene rearrangement, EGFR downstream signaling pathway activation (PI3K-AKT, RAS/RAF), cell cycle-related gene heterogeneity, and pathologic transformation may lead to resistance to third-generation TKIs. To address this, a series of fourth-generation TKIs, such as BLU-945, JBJ-04-125-02, and OBX02-011, are currently under development. New drugs targeting HER2/HER3 have also entered the clinical trial stage. However, the best treatment choice for patients who are resistant to TKI requires further evaluation.

Chemotherapy is the gold standard treatment recommended by the guidelines; however, it has limited patient benefits (6). Immune checkpoint inhibitors (ICIs) are the standard treatment for driver-negative advanced and locally advanced NSCLC (7). However, for patients with EGFR mutations, several clinical trials have shown no evidence to support the benefits of ICIs monotherapy (8-11). The results of the IMpower150 subgroup analysis offer a glimmer of hope for ICIs-based combination therapy (12). In addition, durvalumab has shown some efficacy as a third-line treatment for patients with advanced NSCLC, regardless of the presence of EGFR and anaplastic lymphoma kinase gene mutations (13). Peng et al. detected the expression of programmed death ligand 1 (PD-L1) in specimens before and after resistance in the same patient and discovered that PD-L1 expression in samples after resistance increased from <1% to ≥50% (14). Furthermore, EGFR-TKI administration induces immune microenvironment remodeling, and upregulates antitumor active cells, such as CD8⁺ T cells (15). Although the mechanisms by which EGFR mutations and drug resistance regulate PD-L1 expression remain unknown, immunotherapy should not be forsaken in patients with EGFR resistance. Recently, a series of studies have explored immune-based therapies for EGFR-TKI resistance. A subset of patients who may benefit from immune-based treatments has been defined (12,13,16-21). Observational studies also shown the potential efficacy of ICIs combined with chemotherapy. Beyond immunotherapy-based approaches, an increasing number of clinical trials are investigating post-EGFR-TKI resistance strategies, including antibody-drug conjugates (ADCs) and new-generation TKIs, which may potentially delay immunotherapy implementation. In this context, the therapeutic efficacy of immunotherapy warrants further exploration.

Overall, whether immunotherapy leads to further survival benefits in patients with EGFR-TKI-resistant NSCLC remains unclear. This meta-analysis aimed to explore the efficacy and safety of ICIs combined with other treatments in patients with advanced EGFR-TKI-resistant NSCLC. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-415/rc).

Methods

The protocol has been registered in PROSPERO with the registration number CRD42024568543.

Study eligibility and identification

We searched the PubMed, the Cochrane Library, Web of Science, and EMBASE. The search period was from database creation to March 25, 2025, using the following search keywords: “Immune Checkpoint Inhibitors”, “Carcinoma”, “Non-Small-Cell Lung Mesh”, “EGFR”, and “Randomized clinical trial”.

Data extraction

The key inclusion criteria were as follows: (I) pathologically confirmed locally advanced or metastatic NSCLC with an EGFR mutation; (II) disease progression after EGFR TKI treatment: (i) patients who are resistant to first/second-generation EGFR-TKIs with T790M-negative NSCLC; (ii) patients harboring the T790M mutations who are resistant to third-generation TKI; (iii) patients who developed resistance to third-generation EGFR-TKIs after the initial treatment; (iv) regardless of previous chemotherapy; (III) patients in the intervention group must have received immune-based therapy, whereas those in the control group must have received chemotherapy alone or in combination with other treatments; (IV) the type of study had to be a Phase II or III randomized controlled trial (RCT); (V) studies with Available Data. The exclusion criteria were as follows: (I) studies that did not include eligible patients; (II) incomplete data records; (III) not RCT: review, meta-analysis, animal experiment, case report, and different reports of the study type.

We retrieved the median OS/PFS; HR, and 95% CI of the median OS/PFS; ORR; odds ratio (OR); and safety data from the included studies. Other key basic characteristics included the trial name, year of publication, patients’ clinicopathologic characteristics, EGFR status, and specific drugs used for treatment. Two authors (Xiaojing Zhang, Xiao Zhong) independently screened the literature, extracted the data, and resolved discrepancies via reaching a consensus. After a preliminary screening of titles and abstracts, the potential articles were evaluated for inclusion through full-text evaluation. The screening flowchart is shown in Figure 1.

Figure 1 PRISMA flow diagram of study selection for this meta-analysis.

Statistical analysis

HR and 95% CI were used as effect sizes for the median OS and PFS, whereas OR and 95% CI were used for ORR; and RR and 95% CI were used for safety data. Interstudy heterogeneity was evaluated using Cochran’s Q, and Higgins and Thompson’s I². I²<50% and P>0.05 indicated low heterogeneity of the research results, and a fixed effects model was used for analysis. In contrast, I²>50% and P<0.05 indicated a large heterogeneity between the studies, and the source of heterogeneity was further analyzed. If heterogeneity persisted, a random-effects model was used. Sensitivity analyses were not performed due to the limited number of included studies or consistent low heterogeneity observed in primary analyses.

As for PD-L1 subgroup, HR for OS and PFS, along with their 95% CI, were extracted from the included studies. Pooled HRs were calculated if at least two studies reported data for the same expression threshold. If only one study was available for a given subgroup, the HR and 95% CI were presented directly without reanalysis. Due to limited data, interaction tests could not be reliably performed. All subgroup analyses were considered exploratory. Statistical analysis was performed using R4.3.2 and robvis online tools. The items used to evaluate the risk of bias of the included studies, according to the Cochrane bias risk assessment tool (22), included random sequence generation, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, reporting bias, and other biases.

Results

Database screening identified 1,530 references based on the retrieval strategy, and 12 studies (8,9,12,16-21,23-25) were finally included. A summary of the trial name, year of publication, patients’ clinicopathological characteristics, EGFR status, treatment lines and specific drugs of treatment for each trial is shown in Table 1. Among the included patients, 2,122 had known EGFR mutations and experienced disease progression during or after TKI therapy. Of the 12 included studies, four (8,9,23,24) used treatment regimens of ICIs monotherapy, and eight (12,16-21,25) used immunotherapy combinations. Combination therapies included immunotherapy combined with chemotherapy, and immunotherapy combined with chemotherapy and anti-angiogenic therapy. In the control group, four (8,9,23,24) studies used docetaxel monotherapy, three studies (17,20,21) used pemetrexed in combination with platinum-based chemotherapy, three studies (16,19,25) used placebo plus pemetrexed and platinum-based chemotherapy, and two studies (12,18) used bevacizumab plus carboplatin and paclitaxel.

Median OS

Nine of the twelve studies reported the median OS of patients, and three did not. Compared with chemotherapy, ICIs monotherapy failed to improve OS (HR =1.04, 95% CI: 0.79–1.37, P=0.79) (Figure 2A). However, chemotherapy combined with other drugs yielded marginal benefits in terms of OS (HR =0.88, 95% CI: 0.79–0.99, P=0.03). This benefit was derived from ICIs combined with chemotherapy (HR =0.86, 95% CI: 0.75–1.00, P=0.045), but there was no benefit when this regimen was combined with anti-angiogenic drugs (HR =0.91, 95% CI: 0.76–1.10, P=0.34) (Figure 2B). In Impower150, compared with anti-angiogenic drugs plus chemotherapy, neither ICIs plus chemotherapy and anti-angiogenic drugs (HR =0.74, 95% CI: 0.38–1.46, P=0.38) nor ICIs plus chemotherapy (HR =1.22, 95% CI: 0.68–2.22, P=0.51) showed any benefit (Table 2). It should be noted that the combined HR in Figure 2 reflects the overall trend across all studies and does not represent the efficacy of each specific regimen. Three studies reported a PD-L1 subgroup analysis; no OS benefit was observed from immune-based therapy or ICIs monotherapy versus chemotherapy regardless of PD-L1 expression (Table 3).

Figure 2 Forest plot of HR comparing OS in patients who received ICIs vs. chemotherapy. (A) Summary hazard ratios in monotherapy group. (B) Subgroup analysis according to administration scheme in ICI-based combination therapy group. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; IV, inverse-variance; OS, overall survival; SE, standard error.

Median PFS

Ten of the twelve studies reported the median PFS of patients. The chemotherapy group was used as the control. Conventional chemotherapy demonstrated a significant prolongation of PFS, compared with ICIs monotherapy (HR =1.73, 95% CI: 1.30–2.29, P<0.001) (Figure 3A). The pooled results showed that ICIs-based combination therapy prolonged PFS, with a pooled HR of 0.65 (95% CI: 0.58–0.72, P<0.001). Subgroup analysis based on combination regimens showed that the combination of ICIs and chemotherapy was beneficial in prolonging PFS (HR =0.76, 95% CI: 0.66–0.87, P<0.001). Notably, it can be speculated from the HR that the effect of ICIs plus anti-angiogenic agents and chemotherapy (HR =0.51, 95% CI: 0.43–0.61, P<0.001) was better than ICIs plus chemotherapy alone (Figure 3B). However, further clinical trials are needed to confirm these benefits. In Impower151, ICIs plus chemotherapy and anti-angiogenic versus anti-angiogenic drugs plus chemotherapy showed no significant difference in PFS (HR =0.86, 95% CI: 0.61–1.21, P=0.39) (Table 2). In subgroup analysis of PD-L1 expression, PD-L1 ≥1% and PD-L1 ≥50%, a regiment of ICIs plus chemotherapy and anti-angiogenic agents could generate significant efficiency in PFS (HR =0.47, 95% CI: 0.25–0.87, P=0.01; HR =0.24, 95% CI: 0.07–0.84, P=0.02) (Table 3). Notably, only one study reported this result in 215 patients.

Figure 3 Forest plot of HR comparing PFS in patients who received ICIs vs. chemotherapy. (A) Summary hazard ratios in monotherapy group. (B) Subgroup analysis according to administration scheme in ICI-based combination therapy group. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; IV, inverse-variance; PFS, progression-free survival; SE, standard error.

ORR

Seven out of the twelve studies provided data on patients’ ORR. Among these studies, only one study presented ORR data for the ICIs monotherapy group, while our meta-analysis focused solely on the combination group (Figure 4A). The findings revealed that ICIs-based combination therapy had a better ORR than chemotherapy (OR =1.76, 95% CI: 1.11–2.79, P=0.03). Subgroup analyses showed that ICIs plus chemotherapy did not show a better ORR than chemotherapy (OR =1.21, 95% CI: 0.89–1.64, P=0.22) (Figure 4B), but the ORR in the ICIs plus anti-angiogenic drugs and chemotherapy group was significantly better than that in the chemotherapy group (OR =2.25, 95% CI: 1.70–2.97, P<0.001) (Figure 4C).

Figure 4 Forest plot of OR comparing ORR in patients who received ICI-based combination therapy vs. chemotherapy. (A) Summary OR in ICI-based combination therapy group. (B) Summary OR in ICIs plus chemotherapy group. (C) Summary OR in ICIs plus anti-angiogenesis agents and chemotherapy group. CI, confidence interval; ICI, immune checkpoint inhibitor; MH, Mantel-Haenszel; OR, odds ratio; ORR, objective response rate.

Safety

When analyzing the included studies, we examined treatment-related adverse events (TRAEs) of all grades, those of grade ≥3, and the TRAEs leading to treatment discontinuation. Comparison with traditional chemotherapy revealed that ICIs monotherapy did not result in more severe adverse reactions, encompassing all-grade TRAEs (RR =0.78, 95% CI: 0.75–0.82, P<0.001), grade ≥3 TRAEs (RR =0.35, 95% CI: 0.17–0.72, P=0.02) or TRAEs leading to discontinuation (RR =0.56, 95% CI: 0.23–1.36, P=0.13) (Figure 5). In the ICIs combination therapy group, no statistically significant difference was observed in all-grade TRAEs compared to the chemotherapy group (RR =1.34, 95% CI: 0.71–2.54, P=0.27). However, combination therapy was associated with more grade ≥ 3 TRAEs (RR =1.33, 95% CI: 0.80–2.22, P=0.19) and TRAEs leading to discontinuation (RR =1.57, 95% CI: 1.25–1.99, P<0.001) (Figure 6). In IMpower150 and IMpower151, compared with anti-angiogenic drugs plus chemotherapy, ICIs plus chemotherapy and anti-angiogenic agents showed no statistically significant difference in all-grade TRAEs (RR =1.01, 95% CI: 0.70–1.46, P=0.82) and grade ≥ 3 TRAEs (RR =1.09, 95% CI: 0.95–1.24, P=0.23), whereas higher risk of discontinuation (RR =1.76, 95% CI: 1.17–2.63, P=0.006) (Figure 7).

Figure 5 Forest plot of RR comparing TRAEs in patients who received ICIs monotherapy vs. other therapeutics. (A) Summary RR of all-grade TRAEs. (B) Summary RR of grade ≥3 TRAEs. (C) Summary RR of TRAEs leading to discontinuation. CI, confidence interval; ICI, immune checkpoint inhibitor; MH, Mantel-Haenszel; RR, risk ratio; TRAEs, treatment-related adverse events.

Figure 6 Forest plot of RR comparing TRAEs in patients who received ICI-based combination therapy vs. other therapeutics. (A) Summary RR of all-grade TRAEs. (B) Summary RR of grade ≥3 TRAEs. (C) Summary RR of TRAEs leading to discontinuation. CI, confidence interval; ICI, immune checkpoint inhibitor; MH, Mantel-Haenszel; RR, risk ratio; TRAEs, treatment-related adverse events.

Figure 7 Forest plot of RR comparing TRAEs in patients who received ICIs plus anti-angiogenesis agents and chemotherapy vs. anti-angiogenesis agents plus chemotherapy. (A) Summary RR of all-grade TRAEs. (B) Summary RR of grade ≥3 TRAEs. (C) Summary RR of TRAEs leading to discontinuation. CI, confidence interval; ICIs, immune checkpoint inhibitors; MH, Mantel-Haenszel; RR, risk ratio; TRAEs, treatment-related adverse events.

Heterogeneity and bias

We observed low heterogeneity with respect to the median OS (I²=0%, P=0.74 for monotherapy; I²=0%, P=0.89 for combination therapy), median PFS (I²=0%, P=0.70 for monotherapy; I²=57%, P=0.03 for combination therapy), and ORR (I²=60%, P=0.03) among the included studies (Figures 2-4). The results obtained using the Cochrane risk-of-bias assessment tool for the 12 enrolled RCTs are presented in Figure S1.

Discussion

In this meta-analysis, the efficacy of ICIs and ICIs-based combination therapies in patients with EGFR-TKI-resistant NSCLC was systematically reviewed and evaluated. ICIs monotherapy as a second- or third-line treatment showed no benefit in terms of OS and PFS compared with chemotherapy, which is consistent with previous studies (26-28). Patients with EGFR mutation have lower PD-L1 expression, CD8⁺ TILs, and tumor mutation burden, which leads to a worse effect of ICIs (29,30). However, EGFR-TKIs may remodel the immune microenvironment by upregulating PD-L1 expression and activating CD8+ T and NK cells (14,15), which provides a theoretical basis for subsequent immunotherapy in patients with NSCLC after EGFR-TKI resistance. An in-depth analysis based on the MCID framework (31) revealed that ICIs-chemotherapy combinations demonstrated clear clinical value, with PFS showing an HR of 0.76 (95% CI: 0.66–0.87) which reached a medium effect size (Cohen’s d=0.3) and met the predefined MCID threshold (HR ≤0.76), while OS exhibited a HR of 0.86 (95% CI: 0.75–1.00) that approached but did not quite reach the small effect size threshold (HR =0.83), indicating meaningful though somewhat differential clinical benefits across these endpoints. Our findings are consistent with the results reported by Long et al., whose retrospective analysis of advanced NSCLC patients following osimertinib progression demonstrated significantly prolonged median progression-free survival (6.4 vs. 2.8 months; HR =0.41, 95% CI: 0.20–0.82) and overall survival (12.8 vs. 10.5 months; HR: 0.39, 95% CI: 0.19–0.80) in the ICIs-plus-chemotherapy group compared to chemotherapy alone (32). In a study comparing ICIs-based combination therapy to ICIs monotherapy in patients with previous EGFR-TKI progression, the median PFS were 5 and 2.2 months and median OS were 14.4 and 7 months, respectively, suggesting that the ICIs-based combination therapy was better than ICIs monotherapy (33). The mechanism may involve chemotherapy enhancing immune response by modulating the effector T cell/regulatory T cell ratio (34).

The formation of peritumoral blood vessels may be a reason for poor immunotherapy results. Vascular endothelial growth factor (VEGF) is a key player in promoting angiogenesis by interacting with its receptor VEGFR2, which is the primary target for anti-angiogenic therapy (35,36). VEGF contributes to the creation of a local and systematic immunosuppressive environment through several pathways, such as aiding tumor cells in evading immunosurveillance and inducing neovascularization that leads to an acidic and hypoxic tumor microenvironment (TME). Therefore, even if ICIs activate more immune cells, it is difficult for them to exert significant effects. Anti-angiogenic drugs promote vascular normalization, which enables immune cell infiltration into the TME by preventing tumor neovascularization. This process boosts the efficacy of immunotherapy against cancer (35-37). In our analysis, ICIs plus anti-angiogenic agents and chemotherapy simultaneously significantly improved the PFS and ORR compared with chemotherapy alone. However, this treatment regimen did not prolong OS; this result may be attributed to the limited number of participants [215] in that trial. VEGF inhibition normalizes vasculature, potentially improving immune cell infiltration, but excessive suppression might exacerbate hypoxia or alter immune cell function, counteracting OS benefits despite PFS gains (36). The study by Horita et al. emphasizes the importance of flexible MCID in evaluating non-interval scale effect sizes (such as HR), which provides theoretical support for interpreting the findings of our current research. Their methodological framework suggests that differentiated MCID criteria may be required for endpoints with distinct temporal dimensions like PFS and OS, offering significant implications for future study design (31).

Our analysis showed the benefit of the combination of ICIs, chemotherapy, and anti-angiogenic agents in terms of PFS compared with chemotherapy alone. However, it is currently unclear which drug combination can exert the greatest anti-tumor effect. IMpower150 subgroup analysis showed that the median OS was longer in the ABCP (27.8 months) than that in the BCP (18.1 months) arm, despite not reaching statistical significance (12). In the IMpower151 trial, ABCP and BCP showed no significant differences in terms of PFS (18). Therefore, more clinical trials are needed to determine combination drug regimens.

Regarding safety, the use of ICIs monotherapy did not increase occurrence of severe TRAEs, compared to chemotherapy. No notable variance was observed in the occurrence of all-grade TRAEs between the combination therapy and control cohorts. However, the incidence of grade ≥3 TRAEs and TRAE leading to discontinuation was elevated in the combined treatment group relative to the chemotherapy group. Notably, the incidence of AEs was lower with ivonescimab than that with other ICIs-based combination therapies, probably because of its macromolecular properties, which are less likely to be distributed in the peripheral blood, thereby reducing toxicity due to off-target effects. TRAEs of grade 3 or higher in the combination therapy group included neutropenia, anemia, hypertension, and leukopenia, with no new safety concerns identified. Therefore, the health status of the patients in the combination therapy group should be closely monitored.

In addition, this meta-analysis showed that the therapeutic efficacy of ICIs was influenced by the proportion of PD-L1 tumors. Among the included studies, only three reported OS in patients with different tumor proportions of PD-L1 in the immunotherapy group. In patients with PD-L1 tumor proportion score (TPS) ≥1%, the combination of ICIs with chemotherapy significantly improved PFS compared to chemotherapy alone, but no OS benefit was observed. Regardless of PD-L1 expression status, neither ICI monotherapy nor ICI combined with chemotherapy and anti-angiogenic therapy demonstrated improved survival outcomes over chemotherapy alone. One study reported that the PFS of combination therapy was significantly better in the combination of PD-1 Inhibitors, antiangiogenic drugs, and chemotherapy group than that in the chemotherapy group in a population with PD-L1 expressions of ≥1% and ≥50% (21).

Beyond immunotherapy, Multiple clinical studies have provided evidence for the effectiveness of combination treatment strategies in overcoming resistance in advanced EGFR-mutant NSCLC. The MARIPOSA clinical trial evaluated amivantamab combined with lazertinib (a third-generation EGFR tyrosine kinase inhibitor) versus osimertinib monotherapy as first-line treatment for EGFR-mutated NSCLC (Del19 or L858R variants). Results demonstrated significantly longer median PFS with the combination therapy (23.7 months) compared to osimertinib alone (16.6 months) (38). Building on these findings, the subsequent MARIPOSA-2 trial revealed that patients who developed osimertinib resistance and received amivantamab plus chemotherapy (with or without lazertinib) achieved better PFS outcomes than those treated with chemotherapy alone (39). These phase III trial results led to FDA approval of amivantamab for both treatment-naïve and osimertinib-resistant EGFR-mutant NSCLC cases. For MET-driven resistance, combinations of osimertinib with MET inhibitors such as savolitinib, capmatinib, or tepotinib have yielded encouraging outcomes. The TATTON trial demonstrated that pairing osimertinib with MET inhibitors enhanced response rates in patients exhibiting MET amplification. Several phase II and phase III clinical trials are currently underway to evaluate the efficacy of ADCs in patients with EGFR-mutant NSCLC who have experienced disease progression (40).

The phase III HERTHENA-Lung02 trial assessing HER3-DXd in patients with EGFR-mutant NSCLC who have experienced disease progression during treatment with an EGFR TKI and cisplatin-based chemotherapy is currently ongoing (41). As of September 2024, interim results from this trial demonstrated a statistically significant increase in PFS compared to platinum-based chemotherapy, although OS data were still immature at that point. No new safety concerns were identified in the HER3-DXd arm, aside from a few reports of interstitial lung disease. In the phase III TROPION-Lung01 trial, Dato-DXd significantly extended PFS relative to docetaxel; however, no improvement in OS was observed in this study (41).

This study focused on EGFR-mutant NSCLC patients with prior TKI therapy, ensuring a degree of population homogeneity. However, this meta-analysis has certain limitations. It only included multi-arm RCTs and excluded several single-arm trials, resulting in a limited pool of trials. The lack of information on EGFR mutation type, previous TKI treatment lines, and the limited investigation of PD-L1 expression in this meta-analysis hindered the comprehensive assessment of treatment outcomes. Due to the scarcity of relevant data in the literature, the impact of these variables could not be thoroughly evaluated. Therefore, future clinical trials are warranted to gather comprehensive data, and provide an in-depth analysis of the therapeutic benefits of ICIs in this patient population. Further research is needed to explore the potential of ICIs in patients lacking the T790M mutation, or in those who have progressed after T790M inhibitor therapy.

Conclusions

In patients with EGFR-TKI-resistant NSCLC, the combination of ICIs with chemotherapy significantly improved both PFS and OS compared to chemotherapy alone, while ICIs, chemotherapy, and anti-angiogenic drugs only enhanced PFS. The ICIs-chemotherapy regimen demonstrates acceptable safety, representing a feasible therapeutic option for this population.

Acknowledgments

We express our gratitude to the patients for their participation in the clinical trial and to the investigators for releasing the clinical data.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-415/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-415/prf

Funding: This research was supported by National Natural Science Foundation of China (grant No. 82172865), Start-up fund of Shandong Cancer Hospital (grant No. 2020-B14), Clinical Research Special Fund of Wu Jieping Medical Foundation (grant Nos. 320.6750.2021-02-51 and 320.6750.2021-17-13), The Key Research and Development Program of Shandong (Major Science & Technology Innovation Project) (grant No. 2021SFGC05012021).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-415/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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