Cancer surgery-induced immune dysfunction provides a theoretical basis for the use of ICI as adjuvant therapy (24). Surgical resection induces inflammatory responses and metabolic events (25). As a result, altered cytokine levels occur, and Th1 cytokines (IL-2, IL-12 and IFN-γ) are suppressed, but Th2 immunity is increased (IL-10, IL-6/8, TNF-α) (26–28), which is characterized by the release of clotting factors, growth factors (such as PDGF, VEGF, TGF-β) and stress hormones (prostaglandins, catecholamines) (28). These events are key regulators of wound healing and pain control, and they can also lead to the rapid expansion of myeloid-derived suppressor cells (MDSCs), M2 macrophages and T regulatory cells (Tregs) (24). Cellular immune suppression leads to the expression of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) (29), T-cell dysfunction (30–32) and NK-cell functional impairment (33, 34), overall resulting in postoperative immunosuppression in the patient ( Figure 1 ). Alongside surgical trauma, other postoperative factors, such as hypothermia, blood loss and sepsis, contribute to immunosuppression (24). In contrast, ICI can block the binding of PD-1 and PD-L1, upregulate the growth and proliferation of T cells, enhance the recognition of tumor cells by T cells, and activate their attack and killing functions, thus realizing their antitumor effect.

The combination of chemotherapy with immunotherapy may have a synergistic effect and is more effective in removing postoperative minimal residual disease (3) ( Figure 1 ). A normal immune response requires the ability of T cells to recognize nonself antigens (antigenicity) and innate immune cells to sense danger signals in the environment (adjuvanticity). These processes activate the innate immune system, promote dendritic cell maturation, and eventually activate effector T cells. The third function of the immune system is homeostatic feedback inhibition, which can curb the immune response in a timely manner to prevent immune-mediated self-damage after the clearance of pathogens. Cancer has developed numerous strategies to modulate the normal immune response (35). For example, a loss of tumor antigen expression or presentation contributes to tumor immune evasion. Danger signals released by dying cancer cells promote cancer inflammation. The infiltration of immunosuppressive cells, the release of immunosuppressive molecules and the stimulation of feedback inhibition by various checkpoint molecules eventually activate the formation of an immunosuppressive microenvironment. Tumor cells disrupt the discriminatory functions of the immune response to evade elimination through the following mechanisms: (I) reduced class I MHC expression or genetic loss of B2-microglobulin to prevent cell surface presentation of T cells recognizing tumor-associated antigens (TAAs); (II) tumor cells may inhibit cell-intrinsic activation of pattern recognition receptor (PRR) signaling through the genetic loss or silencing of pathways such as cGAS/STING; and (III) the feedback mechanisms that suppress normal immune responses can be exploited by tumor cells.

Chemotherapy can exert immunomodulatory effects not only by affecting tumor cells but also by increasing immunogenicity and increasing T-cell infiltration (36, 37). Cancer cells with innate or experimentally enforced defects cause immunogenic cell death (ICD). The adaptability of chemotherapy is enhanced by the induction of ICD. ICD can be induced by different stressors, including (I) pathogens; (II) physical modalities, encompassing high hydrostatic pressure, severe heat shock, various forms of ionizing radiation, etc.; (III) chemotherapeutics such as anthracyclines and DNA-damaging agents; and (IV) targeted anticancer agents such as the epidermal growth factor receptor-specific monoclonal antibody cetuximab. The mechanism of chemotherapy-driven ICD is as follows (38): In response to chemotherapeutic agents, malignant cell surfaces express calreticulin (CALR) and other endoplasmic reticulum (ER) chaperones and secrete ATP, resulting in a type I interferon (IFN) response that stimulates the production of CXC-chemokine ligand 10 (CXCL10) and releases high-mobility group Box 1 (HMGB1) and annexin A1 (ANXA1). These processes facilitate the uptake of cell corpses and fragments by antigen-presenting cells, including dendritic cells (DCs), and lead to the activation of the adaptive immune response involving T cells.

In advanced NSCLC, the combination of an immune checkpoint inhibitor and either pemetrexed or paclitaxel with cisplatin- or carboplatin-based chemotherapy as first-line therapy obtains significant therapeutic effects. At present, among adjuvant ICIs in combination with chemotherapy, the chemotherapy regimen is mostly based on platinum-based compound. The immunogenic effects of platinum compounds include the following four aspects (3, 39) ( Figure 1 ): (I) the induction of ICD; (II) the downregulation of PD-L1 and PD-L2 on DCs and the improvement in their T-cell activation potential; (III) the inactivation of the STAT pathway, thereby decreasing the expression of PD-L2 on cancer cells; and (IV) the upregulation of the M6P receptor on tumor cells, leading to tumor cell killing by the granzyme-B of activated T cells.

The BR31/IFCT1401 trial is a double-blind phase III trial involving patients with completely resected NSCLC (stage IB–IIIA, American Joint Committee on Cancer (AJCC) 7th tumor node metastasis (TNM) stage), initiated in October 2014 with a completion date of January 2024 (40). A total of 1415 participants are estimated to be enrolled, and patients with NSCLC with EGFR mutations or ALK rearrangements are not excluded. After receiving optional adjuvant chemotherapy, participants are randomized to receive either durvalumab or placebo for a year. The primary outcome measures include disease-free survival (DFS) for patients with NSCLC with PD-L1 expression TC ≥25% and patients with NSCLC without EGFR mutations or ALK rearrangements.

The IMpower010 trial was launched in October 2015 and has an estimated completion date of December 2027. It is an open-label phase III study with a sample size of 1280 patients with resected NSCLC (stage IB–IIIA, AJCC 7th TNM stage) from 227 sites in 22 countries (41). This trial also includes patients with NSCLC tumors with EGFR mutations or ALK rearrangements. After completing up to four cycles (q3w) of adjuvant cisplatin-based chemotherapy, eligible participants are randomized to receive atezolizumab for 16 cycles (q3w) or best supportive care. The primary outcome is DFS, for which the results have been published previously (41).

This phase III trial was initiated in November 2015 and is scheduled to be completed in February 2024. A total of 1177 patients with resected NSCLC (stage IB–IIIA, AJCC 7th TNM stage) (42) are enrolled in the study. After completing optional adjuvant chemotherapy, participants are randomized to receive adjuvant pembrolizumab or placebo every 3 weeks for one year. Furthermore, NSCLC patients with EGFR/ALK (+) tumors were not excluded. The primary endpoint of the study is DFS.

A total of 903 participants with resected NSCLC (stage IB-IIIA, AJCC 7th TNM stage) are enrolled in this trial (43), which was launched in May 2016 and is scheduled to be completed in July 2024. Patients with EGFR/ALK wild-type tumors were included in this study. After optional chemotherapy and radiotherapy, participants are randomized to receive adjuvant nivolumab every 4 weeks or observation for one year. The primary outcomes are DFS and OS. The secondary outcome measure is the incidence of toxicity grade.

The ALCHEMIST Chemo-IO Study was launched by the National Cancer Center in June 2020 with an estimated completion date of December 2024 (44). It is estimated to enroll 1210 stage IIA–IIIB (AJCC 8th TNM stage) participants with NSCLC without EGFR mutations or ALK rearrangements (applicable only to patients with nonsquamous tumors). Patients will be randomized to one of 3 treatment arms: chemotherapy-immunotherapy with pembrolizumab during (4 cycles, q3w) and after (12 cycles, q6w) chemotherapy, sequential chemotherapy (4 cycles, q3w) followed by pembrolizumab (16 cycles, q6w), or chemotherapy alone (4 cycles, q3w). The primary endpoint is DFS.

As a phase III, multicenter, double-blind study initiated in July 2020, MERMAID-1 will recruit approximately 332 MRD-positive patients with completely resected stage II–III NSCLC (AJCC 8th TNM stage) without EGFR mutations or ALK rearrangements (45). Patients will be randomized to receive adjuvant durvalumab plus standard of care (SOC) chemotherapy or placebo plus SOC chemotherapy (4 cycles (q3w) followed by 12 cycles (q4w)). The primary outcome measure is DFS in the MRD-positive analysis set, and the estimated study completion date is September 2026.

The MERMAID-2 trial is a phase III, multicenter double-blind study launched in November 2020 (46) with an estimated completion date of October 2027. A total of 284 participants are estimated to be enrolled in the study. After complete resection, patients with stage II–III NSCLC (AJCC 8th TNM stage) without EGFR mutations or ALK rearrangements will be regularly monitored for the presence of MRD via the analysis of circulating tumor DNA levels in plasma samples. Patients who become MRD+ during the surveillance period and have no disease recurrence visible on imaging will be randomized 1:1 to receive adjuvant durvalumab or placebo every 4 weeks for up to two years or until investigator-assessed disease recurrence. The primary endpoint is DFS in patients with PD-L1 tumor cell expression (TC) ≥ 1%.

The NADIM-ADJUVANT trial is an open-label, randomized, two-arm, phase III, multicenter clinical trial (47) that was launched in January 2021 with an expected completion date of April 2028. A total of 210 participants (stage IB-IIIA NSCLC without EGFR mutations or ALK rearrangements) are estimated to be recruited. Patients will be randomized to one of 2 treatment arms: chemotherapy-immunotherapy with nivolumab during (4 cycles, q3w) and after (6 cycles, q4w) chemotherapy or chemotherapy alone (4 cycles, q3w). The primary endpoint is DFS. This trial was launched by January 2021 and will be completed in April 2028.

This study is a randomized, double-blind, controlled phase III trial in regard to adjuvant toripalimab versus placebo combined with chemotherapy for EGFR/ALK mutation-negative stage II-IIIB (N2) (AJCC 8th TNM stage) NSCLC (48). After adjuvant chemotherapy (4 cycles, q3w), 341 patients were randomized to receive adjuvant toripalimab or placebo for 4 cycles (q3w). The primary endpoint is DFS, and this trial will be completed in December 2027.

As we all know, not all patients experience favorable survival benefits from immunotherapy. Therefore, it is important to identify patients most likely to benefit from adjuvant immunotherapy. The IMpower010 trial results suggested that PD-L1-positive (TC ≥1%) NSCLC patients can benefit from atezolizumab treatment. However, subgroup analysis showed that there was no significant difference in DFS between patients with PD-L1 expression of 1–49% in the atezolizumab group and the best supportive care group, indicating that the benefit of all groups was mainly derived from the group with high PD-L1 expression (TC ≥50%) (41). On the other hand, the KEYNOTE-091 study results were seemingly contradictory. The results showed that DFS was significantly improved in patients receiving pembrolizumab in the all-comer population, regardless of PD-L1 expression, but PD-L1 TC ≥50% NSCLC patients did not exhibit a survival benefit (59, 61). In conclusion, the predictive role of PD-L1 expression for adjuvant immunotherapy remains to be established. The ctDNA-based MRD was considered another potential biomarker for predicting the benefit of adjuvant therapy. In a cohort of 26 MRD-positive NSCLC patients, Liang et al. found that patients who received adjuvant treatment had significantly improved recurrence-free survival (RFS) compared with those who did not receive adjuvant treatment (HR=0.3; P=0.008) (62). Similarly, Zhang et al. revealed that patients with undetectable MRD might not benefit from adjuvant treatment in subgroup analyses (63). Furthermore, the MERMAID-1 and MERMAID-2 studies were launched in 2020 to evaluate the clinical application value of ctDNA-based MRD in predicting the benefits of adjuvant immunotherapy in NSCLC patients (45, 64). Finally, according to previous studies, blood-based TMb (65), tumor infiltrating lymphocytes (66) and specific gene mutations such as STK11, KEAP1 and TP53 (67) have been reported as biomarkers predictive of the benefits of ICI treatment. However, the value of those biomarkers for predicting the benefits of adjuvant immunotherapy are not clear, and more data are needed for validation.

After the ADAURA study (6), osimertinib was approved as the standard adjuvant therapy for patients with stage IB-IIIA tumors with EGFR mutations (68). However, it is unclear whether there are patients with some oncogenes such as ALK rearrangements, KARS, STK11 or TP53 mutations that may benefit from immunotherapy in early stage (69). Furthermore, subsequent analysis from the ADJUVANT/CTONG1104 trial showed that patients with RB1-altered/EGFR-mutant tumors showed better survival with adjuvant chemotherapy than with adjuvant gefitinib (70); therefore, whether these patients can benefit from adjuvant immunotherapy remains to be determined.

A combination of ICI and chemotherapy seemed to be associated with better survival than ICI monotherapy in patients with metastatic NSCLC (71, 72). Therefore, current phase III trials of adjuvant immunotherapy for early-stage NSCLC mainly assess the efficacy of sequential chemoimmunotherapy or concurrent chemoimmunotherapy, except for the MERMAID-2 trial, which evaluates the efficacy of durvalumab monotherapy for MRD+ NSCLC patients ( Figure 2 ). However, whether sequential or concurrent immunochemotherapy provides a better benefit to patients remains unclear. Furthermore, there is no phase III trial comparing single-agent immunotherapy with chemoimmunotherapy. With increasing evidence showing the benefits of adjuvant immunotherapy, there is a need to compare different treatment regimens to optimize adjuvant therapy for early-stage NSCLC.

Currently, the recommended duration of atezolizumab as adjuvant immunotherapy is one year (73). However, as increasing evidence from clinical trials suggests, the duration of adjuvant immunotherapy may be as controversial as the duration of adjuvant targeted therapy, which is recommended to be 2-3 years (6–8). The duration of adjuvant immunotherapy in ongoing clinical trials ranges from 0.5 to 2 years ( Figure 2 ), and we are looking forward to finding optimal patterns for the duration of adjuvant immunotherapy from these clinical trials.

Neoadjuvant immunotherapy is considered another promising approach to improve survival in patients with resectable NSCLC and offers several advantages, such as the downstaging of the tumor, eliminating micrometastases earlier and improving tolerability. Related advances have been detailed in several reviews (64, 74, 75). CheckMate-816 was the first phase III neoadjuvant immunotherapy clinical trial for resectable NSCLC without EGFR mutations or ALK rearrangements (76). The median event-free survival was 31.6 months with nivolumab plus chemotherapy and 20.8 months with chemotherapy alone (P=0.005); the percentages of patients with a pathological complete response were 24.0% and 2.2%, respectively (P<0.001). Furthermore, Zhang et al. reported results for 40 patients with oncogene-mutant NSCLC treated with induction immunotherapy (77). The results suggested that the overall response rate was 62.5%, of which the major pathological response (MPR) rate was 37.5% and the pathological complete response (pCR) rate was 12.5%. The median disease-free survival for all patients with NSCLC with oncogenic mutations and EGFR mutations was 28.5 months. However, due to the overlap of NSCLC populations receiving neoadjuvant and adjuvant immunotherapy and the absence of survival benefit comparison between neoadjuvant and adjuvant immunotherapy, we need more data to help us to make the optimal selection.