The evolving role of neoadjuvant immunotherapy in resectable non-small cell lung cancer: a narrative review

Introduction

Background

Lung cancer is one of the most prevalent malignant tumors and the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80–85% of cases (1). Despite advances in early detection through computed tomography (CT) screening, which has led to an increasing number of patients being diagnosed at an early, resectable stage, the long-term prognosis remains suboptimal. For patients undergoing surgical resection with curative intent, the 5-year survival rates are still unsatisfying, ranging from 60% in stage IIA to as low as 36% in stage IIIA (2). Furthermore, a significant proportion of patients, between 30% and 60%, will eventually develop metastatic disease even after a radical resection (3). This high rate of postoperative recurrence suggests that NSCLC is not merely a localized disease but a systemic one, with micrometastases present at the time of surgery that are undetectable by conventional imaging techniques (4). Adjuvant chemotherapy, administered after surgery, has been shown to improve the 5-year overall survival (OS) rate by only a modest 5% (5). This limited improvement highlights the fundamental shortcomings of relying solely on local treatment and subsequent systemic therapy that may be initiated too late or in patients who are no longer fit for chemotherapy due to postoperative complications. There is, therefore, an urgent and unmet need for novel and more effective treatment strategies that can address the systemic nature of the disease and improve long-term outcomes for patients with resectable NSCLC.

The strategic rationale for neoadjuvant treatment

The traditional perioperative treatment approach for early-stage NSCLC has primarily been surgery followed by adjuvant therapy (6). However, the shift in focus towards neoadjuvant therapy, administered before surgery, represents a fundamental re-evaluation of treatment timing and strategy. This approach offers several key advantages over the conventional adjuvant setting (7). Firstly, neoadjuvant therapy can be delivered when the patient is in a better physical condition, prior to the morbidity and complications associated with major thoracic surgery. This often leads to better patient compliance and a higher rate of completing the full course of systemic therapy (8). Secondly, and perhaps more crucially from a biological standpoint, neoadjuvant therapy provides an early opportunity to address micrometastatic disease. By targeting these subclinical sites of tumor spread early in the therapeutic pathway, there is a greater potential to reduce the risk of distant recurrence (9). Finally, the neoadjuvant setting allows for a real-time assessment of the tumor’s sensitivity or resistance to the administered drugs. The pathological response observed in the resected specimen, such as major pathological response (MPR) and pathological complete response (pCR), can serve as an early, objective indicator of therapeutic efficacy, which can inform subsequent treatment decisions (10). The move towards neoadjuvant therapy is therefore not just a change in the sequence of treatments but a strategic evolution aimed at optimizing patient outcomes by addressing systemic disease upfront and providing early feedback on treatment effectiveness.

The immunologic basis of neoadjuvant immunotherapy

The rationale for using immunotherapy in the neoadjuvant setting is rooted in its unique mechanism of action and the biological advantages conferred by an intact tumor microenvironment (11). Immune checkpoint inhibitors (ICIs), such as anti-programmed death-1 (PD-1) (12), anti-programmed death-ligand 1 (PD-L1) (13), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies (14), function by blocking the immunosuppressive pathways that tumor cells use to evade detection and destruction by the immune system. This blockade “releases the brakes” on the patient’s T-cell response, allowing activated T cells to recognize and attack tumor cells (15). Administering ICIs before surgery leverages the presence of the primary tumor, which acts as a rich source of tumor-associated antigens. When T cells are activated by these antigens in the context of an intact tumor and lymphatic system, they are not only able to infiltrate the primary tumor but also circulate throughout the body via the bloodstream to seek out and eradicate micrometastases (16). This process, often referred to as an “in situ vaccine” effect, can generate a robust and long-lasting systemic immune response. The activated, tumor-specific T cells may then form a pool of memory cells that can patrol the body for years, providing durable protection against future recurrence. This approach has a distinct advantage over adjuvant immunotherapy, which targets a potentially smaller and less-diverse pool of micrometastases after the primary antigenic source has been surgically removed (17). The potential for neoadjuvant immunotherapy to induce this profound and systemic immune memory is a key reason for its growing prominence as a promising strategy for achieving long-term cures in resectable NSCLC. This biological advantage, which leverages the intact primary tumor as an in-situ vaccine to prime systemic immunity, forms the core strategic rationale for prioritizing the neoadjuvant approach over adjuvant therapy. This paradigm shift is further supported by the clinical trials discussed in the following sections. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2184/rc).

Methods

This narrative review was systematically compiled from literature published from 2018 to the present day in PubMed, Embase, and Scopus, and was augmented by searches on Google for recent conference abstracts. The selection process focused on retrieving all pivotal Phase II and III randomized controlled trials (RCTs) that have defined the current standard of care and key concepts (e.g., surrogate endpoints and ctDNA) in the field. This targeted approach aims to synthesize a critical, expert perspective. The search terms used were: “neoadjuvant immunotherapy”, “resectable NSCLC”, “immune checkpoint inhibitors”, “clinical trials”, “pathological complete response”, “event-free survival”, “overall survival”, and “biomarkers” (Table 1). The scope is specifically focused on patients with resectable NSCLC stages IB–IIIB.

Efficacy of neoadjuvant immunotherapy

Immunotherapy monotherapy

Early clinical investigations into neoadjuvant immunotherapy for resectable NSCLC focused on the use of single-agent ICIs to assess their safety and preliminary efficacy (18). The CheckMate 159 trial was one of the first to prospectively explore this approach, administering two cycles of nivolumab to patients with resectable NSCLC (stage IB–IIIA) (19). The results were encouraging, with 9 out of 20 patients (45%) achieving an MPR (20). Another notable monotherapy trial was LCMC3, which evaluated two cycles of atezolizumab in a similar patient population. This study reported an overall MPR rate of 21% but highlighted a potential predictive role for PD-L1 expression, with patients expressing PD-L1 >50% achieving a 33% MPR rate compared to 11% in those with lower expression. Other trials, such as IONESCO (durvalumab) and NEOMUN (pembrolizumab), also demonstrated the feasibility of the monotherapy approach, reporting MPR rates of 19% and 27%, respectively (21,22). While the MPR and pCR rates in these single-agent studies were modest and somewhat heterogeneous, they collectively confirmed that neoadjuvant immunotherapy could be safely administered and was capable of inducing a degree of pathological regression, laying the groundwork for more potent combination strategies. The variability in pathological response rates across these trials suggested that monotherapy alone might not be sufficient for a large proportion of patients, prompting the exploration of more synergistic treatment regimens (23).

Chemo-immunotherapy combinations

The limited but promising results of monotherapy trials paved the way for investigating the synergistic combination of chemotherapy and immunotherapy, which has since become the new standard of care (24). This approach is based on the premise that chemotherapy can induce immunogenic cell death and release neoantigens, effectively “priming” the immune system for a more robust response to ICIs (25). The NADIM trial, which administered neoadjuvant nivolumab plus chemotherapy to patients with stage IIIA NSCLC, provided some of the earliest compelling evidence for this synergy, achieving a remarkable 83% MPR rate and a progression-free survival rate of 87% at 18 months (26). The groundbreaking CheckMate 816 trial, a phase III randomized study, solidified this paradigm shift. It compared neoadjuvant nivolumab plus chemotherapy with chemotherapy alone and demonstrated a statistically significant and clinically meaningful improvement in both event-free survival (EFS) and pCR. The pCR rate was an unprecedented 24% in the combination arm versus only 2.2% in the chemotherapy-alone arm (27). More recent, long-term follow-up data from CheckMate 816 are even more compelling, revealing a significant improvement in OS. At a median follow-up of 68.4 months, the 5-year OS was 65.4% in the nivolumab plus chemotherapy group, compared to 55.0% in the chemotherapy-alone group (28). The AEGEAN trial, another phase III study, further reinforced these findings, showing a clinically meaningful EFS benefit with the addition of perioperative durvalumab to neoadjuvant chemotherapy (HR =0.69) and a trend toward improved OS (29). The profound pathological and survival benefits observed in these large-scale trials have established neoadjuvant chemo-immunotherapy as the definitive front-line treatment for resectable NSCLC. A comprehensive overview of these key trials is provided in Table 2.

Dual immunotherapy combinations

Beyond the chemo-immunotherapy approach, the combination of two different ICIs has also been explored to achieve a more comprehensive activation of the immune system (30). The NEOSTAR trial, a phase II study, investigated neoadjuvant nivolumab alone versus a combination of nivolumab and ipilimumab. The dual immunotherapy arm demonstrated a higher MPR rate of 50% and a pCR rate of 38% compared to the nivolumab monotherapy arm, which had MPR and pCR rates of 24% and 10%, respectively (31). This finding suggested that the complementary mechanisms of PD-1 and CTLA-4 blockade could lead to a more profound pathological response. While the pathological responses were impressive, the clinical value and long-term survival benefits of this approach require further investigation. An exploratory analysis of another CheckMate 816 arm, which compared neoadjuvant nivolumab plus ipilimumab with chemotherapy, showed a 3-year OS rate of 73% versus 61% and an EFS hazard ratio of 0.77 (32). While these results showed a trend towards improved outcomes, they appeared less robust than the confirmed survival benefits of the nivolumab plus chemotherapy arm in the same trial. This outcome suggests that chemotherapy’s role in inducing immunogenic cell death (ICD) and promoting T-cell infiltration may be a superior immune-priming strategy than dual checkpoint blockade alone, or that the higher toxicity associated with anti-CTLA-4 may compromise surgical completion or timing. This discrepancy may be due to differences in patient populations, trial designs, or the biological mechanisms at play, and it highlights the need for ongoing research to define the optimal combination strategy for different patient subsets (33).

While these trials have established the feasibility and efficacy of various neoadjuvant strategies, efficacy outcomes should not be interpreted in a uniform manner across all patients. Beyond overall efficacy, subgroup analyses are increasingly relevant to clinical decision-making (34). For instance, differences have been observed between histological subtypes, with squamous carcinomas showing higher pathological response rates compared with adenocarcinomas in some studies. Patients harboring oncogenic driver mutations, such as EGFR (35) or ALK (36) alterations, generally exhibit attenuated responses to ICIs, highlighting the importance of integrating molecular profiling into treatment planning. In elderly patients or those with poor performance status, while early reports suggest acceptable feasibility, treatment completion rates tend to be lower, and toxicity may be magnified. These nuances underscore the need for tailored strategies in distinct patient populations, rather than a uniform application of neoadjuvant immunotherapy (37).

For patients with actionable driver mutations, such as EGFR or ALK, the benefit of neoadjuvant immunotherapy is less established. The success of adjuvant targeted therapies, such as osimertinib (38) and alectinib (39), has paved the way for investigating these agents in the neoadjuvant setting, which may offer a superior alternative to chemo-immunotherapy for this specific subgroup.

Emerging therapies and biomarkers

The rise of novel combinations: ADCs and beyond

Building on the success of chemo-immunotherapy, the field is rapidly moving toward more innovative combination strategies (40). The phase II NeoCOAST-2 platform study is a prime example of this evolution, designed to efficiently test neoadjuvant durvalumab in combination with novel agents. A notable finding from this multi-arm trial was the exceptional pathological response observed in the arm combining durvalumab with the antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) and chemotherapy (41). This regimen achieved the highest pCR rate of 35.2% and an MPR rate of 63.0%, which were numerically superior to the pCR and MPR rates observed with other immune-novel agent combinations in the study. The rationale for combining ADCs with immunotherapy is supported by their transformative success in other solid tumors, such as the combination of enfortumab vedotin and pembrolizumab in urothelial carcinoma (42) and trastuzumab deruxtecan in breast cancer (43). These precedents highlight the potential of ADCs to induce immunogenic cell death and synergize with checkpoint inhibitors. ADCs, by delivering a cytotoxic payload directly to tumor cells, can induce a specific type of cell death known as immunogenic cell death (ICD) (44). This process releases a wealth of tumor-associated antigens and danger signals that can further amplify the T-cell activation initiated by ICIs. This finding suggests that combining ICIs with targeted therapies that have an immunomodulatory effect may represent the next frontier in neoadjuvant treatment, potentially leading to even higher rates of pathological response and, by extension, improved long-term survival (45). The success of this platform trial model also highlights its efficiency in rapidly identifying promising new regimens for further investigation. Pathological response rates for various neoadjuvant strategies are summarized in Table 3.

The evolution of biomarkers: from PD-L1 to circulating tumor DNA (ctDNA)

The identification of reliable predictive biomarkers is critical for the success of precision oncology (46). PD-L1 expression has been the most widely studied biomarker for immunotherapy to date, and while some studies have shown a correlation between high expression (>50%) and higher response rates, others have demonstrated treatment benefit even in patients with low or negative PD-L1 expression (47). Furthermore, the utility of PD-L1 as a predictive biomarker is complicated by technical challenges, including inter-laboratory heterogeneity, different testing assays, and the spatial and temporal variability of its expression within a tumor. This has led to the recognition that PD-L1 is an imperfect and often unreliable tool for patient selection (48).

In contrast, ctDNA is emerging as a more dynamic and powerful prognostic biomarker, particularly for the detection of minimal residual disease (MRD) (49). The presence of ctDNA in a patient’s bloodstream reflects the systemic burden of the disease. A key finding from the CheckMate 816 trial’s exploratory analysis demonstrated the profound prognostic value of ctDNA clearance after neoadjuvant treatment. Patients who achieved ctDNA clearance had a remarkable 5-year OS rate of 95.3%, whereas those who did not achieve clearance had a significantly lower 5-year OS rate of 52.6% (50). This substantial difference suggests that ctDNA clearance is a more direct and clinically meaningful indicator of effective systemic disease eradication than traditional pathological or radiological assessments (51). While ctDNA clearance is strongly prognostic, its utility in guiding adjuvant treatment decisions-such as withholding therapy in ctDNA-negative patients-remains a hypothesis currently under investigation in adaptive trials. Unlike in the metastatic setting, definitive evidence supporting ctDNA-guided escalation or de-escalation in the curative setting is still emerging (52). This shift from a static, pre-treatment biomarker like PD-L1 to a dynamic, treatment-response-based biomarker like ctDNA represents a major step towards truly personalized medicine in resectable NSCLC. Key biomarkers and their association with clinical outcomes are detailed in Table 4.

Discussion

The debate on endpoints

One of the most significant challenges in conducting clinical trials for early-stage cancer is the long follow-up period required to assess definitive endpoints like OS (53). For years, there has been a debate about the reliability of using pathological response rates, such as MPR and pCR, as surrogate endpoints for long-term survival in the neoadjuvant setting (54). While some studies suggested a correlation between these endpoints and long-term outcomes, a definitive validation was lacking. The clinical significance of pCR is underscored by the landmark 5-year follow-up data from CheckMate 816. Patients who achieved a pCR experienced a 5-year OS rate of 95.3%, compared to 55.7% for those without a pCR. This striking divergence highlights pCR not merely as a pathological finding, but as a transformative prognostic indicator (55).

While the CheckMate 816 trial demonstrated a strong patient-level association between pCR and EFS, the establishment of pCR as a validated trial-level surrogate endpoint remains a subject of ongoing debate. Recent analyses suggest that while pCR is an excellent individual prognostic marker, it may not perfectly predict the magnitude of survival benefit across all trials (56). Nevertheless, this strong association is a major breakthrough because it can significantly accelerate the clinical development and approval of new neoadjuvant regimens. It allows researchers to obtain a strong indication of a drug’s potential efficacy within a much shorter timeframe, enabling new therapies to reach patients more quickly (57). The confirmation of pCR as a validated endpoint sets a new standard for future neoadjuvant clinical trials, shifting the focus from simply reducing tumor size to achieving the most profound pathological response possible, with the expectation of a commensurate survival benefit.

Practical and surgical considerations

While neoadjuvant immunotherapy has demonstrated remarkable efficacy, its integration into clinical practice requires careful consideration of practical and surgical aspects (58). The safety and feasibility of surgery after neoadjuvant immunotherapy have been confirmed in numerous studies, with a high rate of complete surgical resection (R0) observed across several trials (59). However, the inflammatory and immunologic changes induced by ICIs can present new challenges for thoracic surgeons. Several studies have reported that neoadjuvant immunotherapy can lead to hilar and mediastinal fibrosis, which may make dissection more technically demanding during surgery and potentially increase the rate of conversion from minimally invasive to open procedures (60). While some studies have reported a low conversion rate, this anatomical alteration underscores the importance of a skilled surgical team and meticulous preoperative planning. The emergence of these surgical complexities highlights that neoadjuvant therapy is not just a medical treatment but a core component of a multidisciplinary approach (61). Surgeons and oncologists must work in close collaboration to manage potential adverse events and optimize the timing of surgery to maximize the likelihood of a successful and safe resection.

For patients identified as poor surgical candidates during the multidisciplinary evaluation, alternative strategies such as stereotactic body radiation therapy (SBRT) or definitive chemoradiation should be considered (62). The ‘bridge-to-surgery’ concept requires careful MDT assessment to ensure patients are not subjected to futile resections (63).

Safety profile and management

The safety of neoadjuvant immunotherapy extends beyond surgical feasibility, encompassing the management of immune-related adverse events (irAEs), which may directly impact treatment completion and perioperative outcomes (64). The most commonly reported irAEs include dermatologic toxicities, thyroid dysfunction, hepatitis, and pneumonitis (65). In large-scale trials such as CheckMate 816, grade 3 or higher irAEs occurred in approximately 10–15% of patients receiving chemo-immunotherapy, compared with less than 5% in monotherapy arms. Perioperative pneumonitis is of particular concern, as it may necessitate delaying surgery (66). In the CheckMate 816 trial, the rate of grade 3–4 pneumonitis was low, reported at approximately 1.3% in the chemo-immunotherapy arm, comparable to chemotherapy alone.

Management typically involves temporary discontinuation of immunotherapy and the initiation of corticosteroids, with prednisone 1–2 mg/kg/day being standard for grade ≥3 events. Immunosuppressive agents such as infliximab may be considered in refractory cases (67). Importantly, early recognition and multidisciplinary coordination are essential to minimize morbidity and ensure safe surgical resection. A practical framework for clinicians is to balance oncologic efficacy with vigilant toxicity monitoring, tailoring perioperative decision-making according to irAE severity (68).

Challenges and unresolved questions

Despite the significant progress, several challenges and unresolved questions remain that require further investigation to fully optimize the neoadjuvant immunotherapy approach.

Optimizing treatment and patient selection

The heterogeneity of treatment response observed across subgroups in clinical trials highlights the importance of patient selection as a central challenge in neoadjuvant immunotherapy (69). As noted earlier, patients with squamous histology often show higher pathological response rates compared with adenocarcinomas, while those harboring oncogenic driver mutations such as epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) typically demonstrate attenuated benefit (70). Similarly, elderly patients or those with impaired performance status may experience greater toxicity and lower treatment completion rates. These subgroup differences emphasize that future strategies must move beyond a uniform application of neoadjuvant therapy toward biomarker-driven, individualized approaches (71). The optimal patient selection remains a matter of debate. While biomarkers like PD-L1 and ctDNA provide valuable insights, they are not perfect predictors of response. The search for a more robust and comprehensive biomarker panel, possibly incorporating tumor mutational burden, gene expression profiles, or even gut microbiome data, is crucial to identify which patients are most likely to benefit from neoadjuvant immunotherapy and which are at risk of toxicity or progression (72). Secondly, the ideal treatment regimen and timing are not yet fully defined. Head-to-head comparisons of different approaches—monotherapy, dual immunotherapy, and chemo-immunotherapy—in various patient subsets are needed to establish the most effective and least toxic strategy for each individual. This includes determining the optimal number of treatment cycles and the ideal time interval between the last dose and surgery (73).

The role of adjuvant therapy after neoadjuvant treatment

A critical unresolved question is the role of additional adjuvant therapy following successful neoadjuvant treatment and surgery. While the neoadjuvant approach has demonstrated its efficacy in addressing micrometastases, it is not yet clear whether all patients require additional systemic therapy after surgery, especially those who achieve a pCR. The use of ctDNA to guide these post-surgical decisions is an area of active investigation. Achieving a pCR is increasingly viewed as a potential trigger for treatment de-escalation. Future trials are exploring whether patients with pCR and ctDNA clearance can safely omit adjuvant therapy, thereby sparing them from unnecessary toxicity (74). A definitive trial is warranted to address this, perhaps by randomizing patients who achieve ctDNA clearance after neoadjuvant treatment to either surveillance or adjuvant therapy, while reserving mandatory adjuvant treatment for those who remain ctDNA positive (75). The ability to monitor ctDNA provides a real-time, quantitative measure of a patient’s response to therapy and may, in the future, be used to identify which patients have persistent MRD and thus require additional adjuvant therapy, or those who have achieved a definitive clearance and can be managed with surveillance alone. This paradigm represents a shift towards a more dynamic and personalized treatment strategy that moves beyond a one-size-fits-all approach (76).

Addressing tumor heterogeneity and resistance mechanisms

The phenomenon of tumor heterogeneity also presents a long-standing challenge, as the diverse nature of cancer cells within a single tumor may lead to varying responses and potential treatment resistance. This heterogeneity can manifest as co-existing oncogenic events and co-mutations that can be responsible for intrinsic resistance to a specific therapy. For instance, mutations in STK11 and KEAP1 have been associated with an ‘immune-cold’ tumor microenvironment and resistance to checkpoint inhibitors, representing a significant challenge for neoadjuvant immunotherapy (77). This demonstrates that not all patients respond equally to a single therapy, even within the same subtype, and emphasizes the need to move from a population-based approach to one tailored to the unique molecular fingerprint of each patient’s tumor. Future research must focus on overcoming these biological and practical hurdles to further refine and personalize the use of neoadjuvant immunotherapy for resectable NSCLC (78).

Practical innovations for biomarkers and surgery

Addressing these challenges requires not only acknowledging their existence but also exploring actionable strategies. Integrating dynamic markers like ctDNA with static tissue markers (PD-L1, TMB) may help overcome the limitations posed by heterogeneity, offering a composite model that captures both the baseline tumor biology and its real-time response to therapy (79). On the surgical front, advances in robotic-assisted thoracic surgery may mitigate the technical difficulties posed by hilar and mediastinal fibrosis after immunotherapy (80). Furthermore, preoperative imaging modalities, including high-resolution CT and PET/CT-based fibrosis scoring, can enable more accurate operative planning and risk stratification (81). These directions represent tangible steps toward resolving current limitations and fostering a more precise and individualized application of neoadjuvant immunotherapy.

Conclusions

Neoadjuvant immunotherapy has fundamentally transformed the treatment landscape for resectable NSCLC, marking a definitive paradigm shift from conventional surgery-first approaches. The evidence from a growing body of clinical trials, particularly the confirmatory phase III studies, has conclusively demonstrated that integrating immunotherapy before surgery is not only safe and feasible but also leads to superior long-term survival outcomes compared to chemotherapy alone. The establishment of neoadjuvant chemo-immunotherapy as the new standard of care is a testament to its powerful synergy and ability to address systemic disease early. The validation of pCR and MPR as reliable surrogate endpoints, as confirmed by the CheckMate 816 trial, will accelerate the pace of innovation, bringing new, effective therapies to patients more rapidly. Looking forward, the trajectory of neoadjuvant immunotherapy in resectable NSCLC is likely to extend far beyond the current paradigm of chemo-immunotherapy. The next stage of progress will be defined by integration—where dynamic biomarkers, such as ctDNA clearance, single-cell immune profiling, and spatial transcriptomics, converge to construct multi-dimensional models for patient selection and treatment monitoring. Therapeutic innovation will also evolve from conventional drug development toward adaptive platform trials capable of rapidly testing novel combinations, including antibody–drug conjugates, bispecific antibodies, and cellular therapies, in the perioperative setting. The ultimate aspiration is not only to increase pathological response and survival, but to achieve durable immune memory that prevents recurrence altogether, positioning neoadjuvant immunotherapy as a curative cornerstone of thoracic oncology. In this sense, the field is entering an era where the boundaries between surgery, systemic therapy, and digital medicine dissolve into a unified framework of precision and personalization.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2184/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2184/prf

Funding: This work was supported by the Shaanxi Provincial Natural Science Foundation General Project (No. S2025-JC-YB-1882) and the Xi’an Municipal Science and Technology Plan Key Medical Research Project (No. 2025JH-YXYJZD-0031).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2184/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/.

References

1. Jovanovic D. Challenges of neoadjuvant targeted therapy in early stage non-small cell lung cancer—a narrative review. AME Surg J 2023;3:16.
2. Lee RM, Rajaram R. Surgical considerations in non-small cell lung cancer patients following neoadjuvant immunotherapy or targeted therapy: a narrative review. Curr Chall Thorac Surg 2025;7:4.
3. Liu W, Zhang T, Zhang Q, et al. A systematic review and meta-analysis of neoadjuvant chemoimmunotherapy in stage III non-small cell lung cancer. BMC Pulm Med 2022;22:490. [Crossref] [PubMed]
4. Hendriks LEL, Remon J, Faivre-Finn C, et al. Author Correction: Non-small-cell lung cancer. Nat Rev Dis Primers 2025;11:3. [Crossref] [PubMed]
5. Banna GL, Hassan MA, Signori A, et al. Neoadjuvant Chemo-Immunotherapy for Early-Stage Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. JAMA Netw Open 2024;7:e246837. [Crossref] [PubMed]
6. West HJ, Kim JY. Rapid Advances in Resectable Non-Small Cell Lung Cancer: A Narrative Review. JAMA Oncol 2024;10:249-55. [Crossref] [PubMed]
7. Bogatsa E, Lazaridis G, Stivanaki C, et al. Neoadjuvant and Adjuvant Immunotherapy in Resectable NSCLC. Cancers (Basel) 2024;16:1619. [Crossref] [PubMed]
8. Zhao ZR, Liu SL, Zhou T, et al. Stereotactic body radiotherapy with sequential tislelizumab and chemotherapy as neoadjuvant therapy in patients with resectable non-small-cell lung cancer in China (SACTION01): a single-arm, single-centre, phase 2 trial. Lancet Respir Med 2024;12:988-96. [Crossref] [PubMed]
9. Cappuzzo F, Wang C, Wang W, et al. 1213P neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS vs. neoadjuvant placebo (PBO) plus CT with adjuvant PBO in resectable non-small cell lung cancer (NSCLC): patient-reported outcomes (PRO) in the RATIONALE-315 trial. Ann Oncol 2024;35:S781-2.
10. Fang M, Luo T, Ji Y, et al. Neoadjuvant hypofractionated radiotherapy plus tislelizumab with anlotinib followed by adjuvant tislelizumab with anlotinib in patients with resectable non-small cell lung cancer (NSCLC): preliminary analysis of a phase II trial (NEO-PIONEER). J Clin Oncol 2025;43:8063.
11. Hu Y, Ren S, Feng J, et al. Real-world comparison of neoadjuvant pembrolizumab plus chemotherapy versus tislelizumab plus chemotherapy in patients with resectable non-small cell lung cancer: a retrospective cohort study of treatment outcomes. Transl Lung Cancer Res 2025;14:467-79. [Crossref] [PubMed]
12. Sun C, Wang X, Xu Y, et al. Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial. EClinicalMedicine 2024;68:102422. [Crossref] [PubMed]
13. Mo DC, Huang JF, Lin P, et al. The role of PD-L1 in patients with non-small cell lung cancer receiving neoadjuvant immune checkpoint inhibitor plus chemotherapy: a meta-analysis. Sci Rep 2024;14:26200. [Crossref] [PubMed]
14. Li MSC, Saw SPL, Addeo A. Anti-CTLA-4 in non-small-cell lung cancer: insights from the NIPPON study. Lancet Respir Med 2024;12:840-2. [Crossref] [PubMed]
15. Yin G, Liu X, Yu X, et al. Analysis of ICIs alone or in combination rechallenged outcomes after progression from first-line ICIs plus chemotherapy in patients with advanced non-small cell lung cancer. Sci Rep 2025;15:30. [Crossref] [PubMed]
16. Liu F, Yin G, Tao Y, et al. The efficacy of ICIs rechallenge in advanced small cell lung cancer after progression from ICIs plus chemotherapy: A real-world study. Int Immunopharmacol 2025;152:114372. [Crossref] [PubMed]
17. Costantini A, Takam Kamga P, Pons-Tostivint E, et al. Soluble PD-L1 (sPD-L1) as a biomarker of durable response and survival in patients with advanced non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitors (ICIs). Cancer Immunol Immunother 2025;74:294. [Crossref] [PubMed]
18. Deng JY, Yang MY, Yang XR, et al. Patterns of failure and the subsequent treatment after progression on first-line immunotherapy monotherapy in advanced non-small cell lung cancer: a retrospective study. BMC Cancer 2024;24:1190. [Crossref] [PubMed]
19. Gómez-Randulfe I, Califano R. The opening gambit: CheckMate 159 and the immunotherapy neoadjuvant era in non-small cell lung cancer. AME Clin Trials Rev 2023;1:17.
20. Liu X, Xing H, Liu H, et al. Current status and future perspectives on immunotherapy in neoadjuvant therapy of resectable non-small cell lung cancer. Asia-pac J Clin Oncol 2022;18:335-43. [Crossref] [PubMed]
21. Eichhorn F, Klotz LV, Bischoff H, et al. Neoadjuvant anti-programmed Death-1 immunotherapy by Pembrolizumab in resectable nodal positive stage II/IIIa non-small-cell lung cancer (NSCLC): the NEOMUN trial. BMC Cancer 2019;19:413. [Crossref] [PubMed]
22. Wislez M, Mazieres J, Lavole A, et al. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO). J Immunother Cancer 2022;10:e005636. [Crossref] [PubMed]
23. Reck M, Remon J, Hellmann MD. First-Line Immunotherapy for Non-Small-Cell Lung Cancer. J Clin Oncol 2022;40:586-97. [Crossref] [PubMed]
24. Gridelli C, Peters S, Mok T, et al. Face to face among different chemo-immunotherapy combinations in the first line treatment of patients with advanced non-small cell lung cancer: Results of an international expert panel meeting by the italian association of thoracic oncology (AIOT). Lung Cancer 2024;187:107441. [Crossref] [PubMed]
25. Rocco D, Gravara LD, Gridelli C. The New Immunotherapy Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer: Reality and Perspectives. Curr Clin Pharmacol 2020;15:11-9. [Crossref] [PubMed]
26. Provencio M, Serna-Blasco R, Nadal E, et al. Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial). J Clin Oncol 2022;40:2924-33. [Crossref] [PubMed]
27. Mitsudomi T, Ito H, Okada M, et al. Neoadjuvant nivolumab plus chemotherapy in resectable non‐small‐cell lung cancer in japanese patients from CHECKMATE 816. Cancer Sci 2024;115:540-54. [Crossref] [PubMed]
28. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol 2021;39:8503.
29. He J, Gao S, Reck M, et al. OA12.06 neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in resectable EGFR-mutated NSCLC (AEGEAN). J Thorac Oncol 2023;18:S72-3.
30. Phillips WJ, Jackson A, Kidane B, et al. Immunotherapy for Early-Stage Non-Small Cell Lung Cancer: A Practical Guide of Current Controversies. Clin Lung Cancer 2025;26:179-90. [Crossref] [PubMed]
31. Cascone T, Leung CH, Weissferdt A, et al. Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial. Nat Med 2023;29:593-604. [Crossref] [PubMed]
32. Wang C, Chen KN, Chen Q, et al. Neoadjuvant nivolumab plus chemotherapy versus chemotherapy for resectable NSCLC: subpopulation analysis of Chinese patients in CheckMate 816. ESMO Open 2023;8:102040. [Crossref] [PubMed]
33. Forde PM, Spicer J, Lu S, et al. Plain language summary of the CheckMate 816 study results: nivolumab plus chemotherapy given before surgery for non-small-cell lung cancer. Future Oncol 2023;19:549-57. [Crossref] [PubMed]
34. Saw SPL, Ong BH, Chua KLM, et al. Revisiting neoadjuvant therapy in non-small-cell lung cancer. Lancet Oncol 2021;22:e501-16. [Crossref] [PubMed]
35. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. [Crossref] [PubMed]
36. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2024;390:1265-76. [Crossref] [PubMed]
37. Isaacs J, Stinchcombe TE. Neoadjuvant and Adjuvant Systemic Therapy for Early-Stage Non-small-Cell Lung Cancer. Drugs 2022;82:855-63. [Crossref] [PubMed]
38. Lv C, Fang W, Wu N, et al. Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial. Lung Cancer 2023;178:151-6. [Crossref] [PubMed]
39. Arter ZL, Nagasaka M. Redefining Recovery: The Transformative Impact of the ALINA Trial on Adjuvant Therapy for ALK-Positive Non-Small Cell Lung Cancer. Lung Cancer (Auckl) 2024;15:129-33. [Crossref] [PubMed]
40. Zhou J, Ma P, Tang Q, et al. The current status and future of ADC therapy for small cell Lung Cancer: a promising approach. J Transl Med 2023;21:808. [Crossref] [PubMed]
41. Cascone T, Bonanno L, Guisier F, et al. Perioperative durvalumab plus chemotherapy plus new agents for resectable non-small-cell lung cancer: the platform phase 2 NeoCOAST-2 trial. Nat Med 2025;31:2788-96. [Crossref] [PubMed]
42. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol 2023;41:22-31. [Crossref] [PubMed]
43. Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med 2022;386:1143-54. [Crossref] [PubMed]
44. Abuhelwa Z, Alloghbi A, Nagasaka M. A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small cell lung cancer (NSCLC). Cancer Treat Rev 2022;106:102393. [Crossref] [PubMed]
45. Marks S, Naidoo J. Antibody drug conjugates in non-small cell lung cancer: An emerging therapeutic approach. Lung Cancer 2022;163:59-68. [Crossref] [PubMed]
46. VanderLaan PA, Rangachari D, Costa DB. The rapidly evolving landscape of biomarker testing in non-small cell lung cancer. Cancer Cytopathol 2021;129:179-81. [Crossref] [PubMed]
47. Yang Q, Chen M, Gu J, et al. Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients. Front Immunol 2021;12:665133. [Crossref] [PubMed]
48. Niu M, Yi M, Li N, et al. Predictive biomarkers of anti-PD-1/PD-L1 therapy in NSCLC. Exp Hematol Oncol 2021;10:18. [Crossref] [PubMed]
49. Dong S, Wang Z, Zhang JT, et al. Circulating tumor DNA-guided de-escalation targeted therapy for advanced non−small cell lung cancer: a nonrandomized controlled trial. JAMA Oncol 2024;10:932. [Crossref] [PubMed]
50. Qi Y, Gu L, Shen J, et al. An open, observational clinical study of neoadjuvant therapy in resectable stage III non-small cell lung cancer. Front Oncol 2023;13:1194100. [Crossref] [PubMed]
51. Jiang T, Ren S, Zhou C. Role of circulating-tumor DNA analysis in non-small cell lung cancer. Lung Cancer 2015;90:128-34. [Crossref] [PubMed]
52. Peng M, Huang Q, Yin W, et al. Circulating Tumor DNA as a Prognostic Biomarker in Localized Non-small Cell Lung Cancer. Front Oncol 2020;10:561598. [Crossref] [PubMed]
53. Shi Q, Sargent DJ. Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials. Int J Clin Oncol 2009;14:102-11. [Crossref] [PubMed]
54. Russo S, Saif MW. Neoadjuvant therapy for pancreatic cancer: an ongoing debate. Therap Adv Gastroenterol 2016;9:429-36. [Crossref] [PubMed]
55. Provencio-Pulla M, Spicer J, Taube JM, et al. Neoadjuvant nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) versus chemo for resectable (IB–IIIA) non-small cell lung cancer (NSCLC): Association of pathological regression with event-free survival (EFS) in CheckMate 816. JCO 2022;40:LBA8511.
56. Sugiyama K, Gordon A, Popat S, et al. Is pathological response an adequate surrogate marker for survival in neoadjuvant therapy with immune checkpoint inhibitors? ESMO Open 2025;10:104122. [Crossref] [PubMed]
57. Fayanju OM, Ren Y, Thomas SM, et al. The Clinical Significance of Breast-only and Node-only Pathologic Complete Response (pCR) After Neoadjuvant Chemotherapy (NACT): A Review of 20,000 Breast Cancer Patients in the National Cancer Data Base (NCDB). Ann Surg 2018;268:591-601. [Crossref] [PubMed]
58. O'Donnell JS, Hoefsmit EP, Smyth MJ, et al. The Promise of Neoadjuvant Immunotherapy and Surgery for Cancer Treatment. Clin Cancer Res 2019;25:5743-51. [Crossref] [PubMed]
59. Zeng J, Yi B, Chang R, et al. Safety and feasibility of robotic-assisted thoracic surgery after neoadjuvant chemoimmunotherapy in non-small cell lung cancer. Front Oncol 2023;13:1134713. [Crossref] [PubMed]
60. Kang J, Zhang C, Zhong WZ. Neoadjuvant immunotherapy for non-small cell lung cancer: State of the art. Cancer Commun (Lond) 2021;41:287-302. [Crossref] [PubMed]
61. Uprety D, Mandrekar SJ, Wigle D, et al. Neoadjuvant Immunotherapy for NSCLC: Current Concepts and Future Approaches. J Thorac Oncol 2020;15:1281-97. [Crossref] [PubMed]
62. Huynh MA, Tang C, Siva S, et al. Review of Prospective Trials Assessing the Role of Stereotactic Body Radiation Therapy for Metastasis-directed Treatment in Oligometastatic Genitourinary Cancers. Eur Urol Oncol 2023;6:28-38. [Crossref] [PubMed]
63. Liu H, Song Y. MDT is still important in the treatment of early stage lung cancer. J Thorac Dis 2018;10:S3984-5. [Crossref] [PubMed]
64. Xie H, Shi X, Wang G. Neoadjuvant immunotherapy for resectable non-small cell lung cancer. Am J Cancer Res 2021;11:2521-36.
65. Vaddepally R, Doddamani R, Sodavarapu S, et al. Review of immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC)—their incidence, management, multiorgan irAEs, and rechallenge. Biomedicines 2022;10:790. [Crossref] [PubMed]
66. Shao L, Lou G. Neoadjuvant immunotherapy in non-small cell lung cancer: a narrative review on mechanisms, efficacy and safety. J Thorac Dis 2022;14:3565-74. [Crossref] [PubMed]
67. Parvathareddy V, Selamet U, Sen AA, et al. Infliximab for Treatment of Immune Adverse Events and Its Impact on Tumor Response. Cancers (Basel) 2023;15:5181. [Crossref] [PubMed]
68. Desai AP, Adashek JJ, Reuss JE, et al. Perioperative Immune Checkpoint Inhibition in Early-Stage Non-Small Cell Lung Cancer: A Review. JAMA Oncol 2023;9:135-42. [Crossref] [PubMed]
69. Watanabe SI, Nakagawa K, Suzuki K, et al. Neoadjuvant and adjuvant therapy for Stage III non-small cell lung cancer. Jpn J Clin Oncol 2017;47:1112-8. [Crossref] [PubMed]
70. Chen D, Jin Z, Zhang J, et al. Efficacy and Safety of Neoadjuvant Targeted Therapy vs. Neoadjuvant Chemotherapy for Stage IIIA EGFR-Mutant Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Front Surg 2021;8:715318. [Crossref] [PubMed]
71. Tao X, Yuan C, Zheng D, et al. Outcomes comparison between neoadjuvant chemotherapy and adjuvant chemotherapy in stage IIIA non-small cell lung cancer patients. J Thorac Dis 2019;11:1443-55. [Crossref] [PubMed]
72. Benitez JC, Remon J, Besse B. Current Panorama and Challenges for Neoadjuvant Cancer Immunotherapy. Clin Cancer Res 2020;26:5068-77. [Crossref] [PubMed]
73. Guo H, Li W, Qian L, et al. Clinical challenges in neoadjuvant immunotherapy for non-small cell lung cancer. Chin J Cancer Res 2021;33:203-15. [Crossref] [PubMed]
74. Day E, Dear PH, McCaughan F. Digital PCR strategies in the development and analysis of molecular biomarkers for personalized medicine. Methods 2013;59:101-7. [Crossref] [PubMed]
75. Dossa F, Acuna SA, Rickles AS, et al. Association Between Adjuvant Chemotherapy and Overall Survival in Patients With Rectal Cancer and Pathological Complete Response After Neoadjuvant Chemotherapy and Resection. JAMA Oncol 2018;4:930-7. [Crossref] [PubMed]
76. Olivier T, Haslam A, Prasad V. Postrecurrence Treatment in Neoadjuvant or Adjuvant FDA Registration Trials: A Systematic Review. JAMA Oncol 2024;10:1055-9. [Crossref] [PubMed]
77. Cai L, Rogers TJ, Mousavi Jafarabad R, et al. High KYNU Expression Is Associated with Poor Prognosis, KEAP1/STK11 Mutations, and Immunosuppressive Metabolism in Patient-Derived but Not Murine Lung Adenocarcinomas. Cancers (Basel) 2025;17:1681. [Crossref] [PubMed]
78. Hu J, Zhang J, Wan S, et al. Neoadjuvant immunotherapy for non-small cell lung cancer: Opportunities and challenges. Chin Med J Pulm Crit Care Med 2024;2:224-39. [Crossref] [PubMed]
79. Pradhan M, Chocry M, Gibbons DL, et al. Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer. Transl Lung Cancer Res 2021;10:590-606. [Crossref] [PubMed]
80. Godoy LA, Chen J, Ma W, et al. Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: current status and perspectives. Biomark Res 2023;11:7. [Crossref] [PubMed]
81. Wu X, Chau YF, Bai H, et al. Progress on neoadjuvant immunotherapy in resectable non-small cell lung cancer and potential biomarkers. Front Oncol 2022;12:1099304. [Crossref] [PubMed]