Tumor cells primarily achieve immune evasion through low immunogenicity and induction of immune suppression. Some tumors lack protein peptides that can be presented by MHC or lose MHC molecules and fail to express co-stimulatory proteins, making them difficult to be recognized by the immune system. Meanwhile, tumor cells secrete immunosuppressive molecules such as TGF-β and IL-10, recruit regulatory T cells, and highly express immune checkpoint ligands, such as PD-L1, which binds to PD-1 on the surface of T cells to inhibit T cell activity. Immune checkpoint inhibitors specifically disrupt immune evasion. CTLA-4 inhibitors can block the inhibitory effect of the CTLA-4 protein, promote the differentiation of naïve T lymphocytes into mature T lymphocytes, and enhance the tumor-killing ability. PD-1/PD-L1 inhibitors, by blocking the binding of PD-1 to PD-L1, enable T lymphocytes to re-recognize tumor cells and restore the immune system’s attack on tumor cells, thereby exerting an anti-tumor effect (24, 25) ( Figure 1 ).

In recent years, clinical studies comparing neoadjuvant immunotherapy combined with chemotherapy to chemotherapy alone have been continuously carried out in esophageal squamous cell carcinoma (ESCC) and other cancers, and have demonstrated positive short-term therapeutic effects and long-term survival benefits. Researchers have explored the mechanism of action of the combination treatment of the two. Previous studies have shown that chemotherapy and immunotherapy play different roles in the process of cancer treatment. Traditional neoadjuvant chemotherapy aims to minimize tumor lesions and achieve preoperative downstaging, while neoadjuvant immunotherapy can eliminate micrometastatic tumor lesions by enhancing the anti-tumor immune response (26).

However, current research has put forward new viewpoints regarding the combination treatment of the two. Among ICIs (immune checkpoint inhibitors), PD-L1 monoclonal antibodies can specifically bind to PD-1, blocking the interaction between PD-1 and its ligands, thereby restoring T-cell-mediated immune responses against tumors. By inhibiting the PD-1/PD-L1 signaling pathway, the antitumor activity of T cells is regulated, enhancing the patient’s own immune system response to the tumor and ultimately achieving the goal of killing tumor cells (27). Among chemotherapeutic drugs, taking albumin-bound paclitaxel as an example, the anti-tumor mechanism of taxanes is to induce and promote the polymerization of tubulin into microtubules, while inhibiting the depolymerization of the formed microtubules. This further leads to abnormal arrangement of microtubule bundles, the formation of asters, damage to the DNA of tumor cells, preventing tumor cells from forming normal mitotic spindles during mitosis, thus inhibiting their division and proliferation and causing tumor cell death. Subsequently, the dead tumor cells release tumor antigens, which are captured by dendritic cells and presented to T cells, thereby activating T cells again (28).( Figure 2 ) In addition, some studies have shown that platinum-based chemotherapeutic drugs can cause DNA cross-linking damage in tumor cells, trigger the DNA damage response (DDR), and activate ATM/ATR kinases, thus directly or indirectly promoting the expression of PD-L1 on tumor cells (29). Therefore, the combination of immunotherapy and chemotherapy has a synergistic effect rather than a simple additive one. This also suggests that different chemotherapy regimens combined with immunotherapy may have an impact on the therapeutic effect.

Immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs may also have a synergistic effect in promoting tumor vascular normalization and stimulating immune activation. Anti-angiogenic drugs (such as apatinib, bevacizumab) can promote the maturation of dendritic cells (DCs) by blocking the VEGF-mediated inhibition of DC maturation, enabling more effective initiation and activation of T cells that bind to tumor antigens. At the same time, they can normalize the structure of tumor blood vessels, thereby facilitating the infiltration of T cells into the tumor. The normalization of tumor blood vessels can promote the aggregation of immune cells and enhance immune function, and the activation of immune cells can, in turn, promote vascular normalization. The combination of the two theoretically can form a positive feedback loop (30, 31)( Figure 3 ).

The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs has shown certain advantages in the short-term efficacy of neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, there are still problems such as a relatively small sample size and the lack of long-term survival outcomes. In recent years, many attempts have been made to use the treatment regimen of immunotherapy combined with anti-angiogenic drugs in other cancers. This combination can significantly improve the objective response rate (ORR) and median progression-free survival (mPFS) of patients, but multiple phase III studies have shown negative overall survival (OS) results (32–34). This poses new challenges to other ongoing trials based on immunotherapeutic drugs, that is, short-term tumor shrinkage does not necessarily bring long-term survival benefits to patients. In this regard, some researchers believe that the combined application of anti-angiogenic drugs and ICIs may have both beneficial and harmful dual effects on tumor immunity. The beneficial effects mainly involve immunostimulatory vascular regulatory effects, which promote the normalization of tumor blood vessels and the formation of an immunostimulatory tumor microenvironment (TME), thus enhancing the anti-tumor immunity. The harmful effects include overpruning of tumor blood vessels, leading to more hypoxia in the TME and further immune suppression, as well as reduced drug biodistribution, which may promote tumor growth and/or metastasis (35).

It is worth noting that in the clinical studies of neoadjuvant immunotherapy combined with chemotherapy, the pathological complete response (pCR) rate generally remains at around 20%. However, the pCR rate in the TD-NICE study is as high as 50%, especially in the NICE study. Even though the included patients had relatively advanced pathological stages, the pCR rate could still reach 39.2%. This may be because the chemotherapy doses in these two studies were higher than those in other clinical studies. In the NICE study, the dose of albumin-bound paclitaxel was 100 mg/m², administered on days 1, 8, and 15. The total dose for 2 cycles reached 600 mg/m². In the TD-NICE study, the total dose of albumin-bound paclitaxel for 3 cycles reached 780 mg/m², along with carboplatin (area under the curve on day 1 = 5).

A retrospective study analyzed the differences in 122 patients with resectable esophageal squamous cell carcinoma (ESCC) after neoadjuvant immunotherapy combined with different chemotherapy dose intensities. All patients received at least 2 cycles of neoadjuvant tislelizumab combined with chemotherapy. The primary endpoints were pCR and major pathological response (MPR), and the secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and disease-free survival (DFS).

The results showed that 99 patients underwent surgery. According to the chemotherapy dose intensity, the patients were divided into three cohorts: Cohort 1 (<80% dose intensity), Cohort 2 (80-90% dose intensity), and Cohort 3 (90-100% dose intensity). The average pCR rate was 22.22%. In Cohort 1, 16% of the patients achieved pCR; in Cohort 2, 17.65% of the patients achieved pCR; and in Cohort 3, 30.00% of the patients achieved pCR. The number of patients who achieved MPR in the three cohorts were 9 (36.00%), 18 (52.94%), and 22 (55.00%) respectively.

In both univariate and multivariate analyses, the dose intensity was significantly correlated with the MPR of patients who underwent esophagectomy (p = 0.048). In terms of survival, the median follow-up time after esophagectomy was 13.76 months. Compared with Cohort 1, Cohorts 2 and 3 had better DFS (p = 0.056). Moreover, the prognosis of patients who achieved MPR was better than that of those who did not achieve MPR (P=0.005) (64). At the same time, the impact of increasing the chemotherapy dose on safety is also within an acceptable range. Therefore, appropriately increasing the chemotherapy dose within the controllable safety range may lead to more significant therapeutic effects.

PD-1/PD-L1 immune checkpoint inhibitors all act on the PD-1/PD-L1 signaling pathway, blocking the binding between tumor cells and T cells, countering the immune escape of tumor cells, restoring and enhancing the function of the body’s immune system, and thus exerting anti-tumor activity (15, 16). The difference between them is that PD-1 inhibitors act on the immune cells (T cells) in the tumor microenvironment. They remove the Fc segment on T cells, avoiding the reduction in the number of T cells, and thus play a role. While PD-L1 acts directly on tumor cells. Therefore, it is necessary to optimize the Fc segment of T cells and retain the function of Fc to further enhance the anti-tumor effect. In addition, different PD-1 or PD-L1 inhibitors have different degrees of modification of the Fc segment (65, 66). These differences also lead to variations in the potential anti-tumor activity and safety of PD-1/PD-L1 immune checkpoint inhibitors. A meta-analysis compared the heterogeneity among different ICI inhibitors. The results showed that neoadjuvant treatment with pembrolizumab and tislelizumab showed higher major pathological response (MPR) rates (pembrolizumab: 72.4%, tislelizumab: 72.2%) and pathological complete response (PCR) rates (pembrolizumab: 41.5%, tislelizumab: 50.0%), while the neoadjuvant treatment based on toripalimab and sintilimab had relatively lower MPR rates (toripalimab: 50.0%, sintilimab: 48.5%) and PCR rates (toripalimab: 18.0%, sintilimab: 26.5%). In terms of safety, the overall incidences of treatment-related adverse events (TRAEs) in the neoadjuvant treatment subgroups of camrelizumab, sintilimab, tislelizumab, and toripalimab were comparable (P=0.30), but the pooled incidence of serious adverse events (SAEs) in the neoadjuvant treatment with pembrolizumab seemed to be lower than that of other ICIs (P=0.01) (67). Therefore, it can be considered that different PD-1/PD-L1 inhibitors may lead to differences in neoadjuvant efficacy and safety. However, due to the different stages of patients included in each study in the meta-analysis and the different chemotherapy regimens, it is still not conclusive at present. In the future, more head-to-head studies of different types of ICIs are needed for verification.

Recently, the long-term follow-up data of the SCALE-1 study, which was successively reported at the 2021 CSCO Congress and the 2022 ASCO Congress, have also been released. This study explored the efficacy and safety of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). The multi-modal combination approach of the SCALE-1 study is different from the traditional neoadjuvant concurrent chemoradiotherapy with immunotherapy, mainly in that the short-course neoadjuvant radiotherapy is arranged between the doses of neoadjuvant immunochemotherapy. That is, on day 1 and day 22, neoadjuvant treatment with toripalimab combined with chemotherapy is used, and neoadjuvant radiotherapy is administered sequentially from day 3 to day 8. Up to now, the 2-year progression-free survival (PFS) rate of this study is 63.8%, and the 2-year overall survival (OS) rate is 78% (21). The good efficacy and innovation of the SCALE-1 study have provided more inspiration for researchers. In multi-modal immunotherapy combinations, adjusting the combination sequence of various modalities to achieve better efficacy and safety has also become a research hotspot in the neoadjuvant treatment of esophageal cancer. In terms of neoadjuvant immunotherapy combined with chemotherapy, some studies have shown that the sequence of preoperative immunotherapy and chemotherapy may also affect the therapeutic effect.

The NCT03985670 study is a single-center, randomized, open-label Phase II clinical study. It enrolled 30 patients with locally advanced resectable ESCC (T3, T4 or positive lymph nodes) and randomly divided them into two groups: receiving chemotherapy on day 1 and immunotherapy on day 3 (experimental group) or receiving chemotherapy and immunotherapy on day 1 (control group). The specific treatment regimen is toripalimab combined with paclitaxel and cisplatin (2 cycles). The primary endpoint is the pathological complete response (pCR) rate, and the secondary endpoints are safety and disease-free survival (DFS) rate.

The results showed that among the 30 patients who completed at least one cycle of neoadjuvant treatment, 11 and 13 patients in the experimental group and the control group, respectively, underwent surgery and all had R0 resection. In the experimental group, 4 patients (36%) achieved pCR, and in the control group, 1 patient (7%) achieved pCR, with no significant statistical difference (P=0.079) (68) However, considering the small sample size of the NCT03985670 study, and the fact that the patient who achieved pCR in the control group was the only one with high PD-L1 expression among all the patients whose PD-L1 expression was detected in this study. Therefore, it can still be considered that in the process of neoadjuvant toripalimab combined with chemotherapy for the treatment of locally advanced resectable esophageal squamous cell carcinoma, delaying toripalimab to the 3rd day after chemotherapy may result in a higher pCR rate compared to using it on the same day.

The therapeutic function of PD-1/PD-L1 monoclonal antibodies is based on enhancing the pre-existing CD8+ T cells. However, patients with esophageal squamous cell carcinoma (ESCC) may have primary and acquired resistance to PD-1/PD-L1 immunotherapy. Patients with primary resistance often show signs at the initial stage of treatment, and at this time, doctors can adjust the treatment according to the patient’s condition. But acquired resistance is often manifested as a significant shrinkage of the tumor at the initial stage of treatment. However, with the deepening of treatment and the increase in the number of treatment cycles, the disease shows stable disease (SD) or progressive disease (PD), thus missing the opportunity for surgery. Therefore, it is necessary to comprehensively understand the mechanism of acquired resistance of tumors and explore methods to overcome acquired resistance.

Studies have shown that inactivating mutations of JAK1/2, methylation of the PD-L1 promoter, and expression of c-Myc are all considered to be the causes of acquired resistance to immune modulators due to the downregulation of PD-L1. Acquired resistance can also be secondary to the downregulation of B2M, leading to a decrease in the expression of major histocompatibility complex class I (MHC-I) and subsequent escape from CD8+ T cells (69). In addition, some studies have shown that acquired resistance is related to T cell exhaustion, because T cell exhaustion is usually driven by high levels of antigens that persist when the host immune response fails to effectively clear them. These T cells have unique transcriptional and epigenetic characteristics, leading to the overexpression of several inhibitory receptors, changes in metabolic adaptation, and dysregulation of cytokine signaling pathways. Among these overexpressed inhibitory receptors is PD-1, which leads to the occurrence of acquired resistance (70–72).

In order to overcome the acquired resistance of immunotherapy, exploring new drug combinations based on the resistance mechanism or developing new ICI drugs is the fundamental solution. In addition, selecting the most appropriate number of neoadjuvant treatment cycles according to the clinical characteristics of patients can also effectively reduce the incidence of acquired resistance. If surgery can be performed before the occurrence of resistance in ESCC patients, it can significantly improve the preoperative objective response rate (ORR) and R0 resection rate of patients, and reduce the occurrence of adverse events. Currently, there is still a controversy regarding the number of neoadjuvant treatment cycles for ESCC patients in clinical practice. ChiCTR2000033761 only reported that the safety of the regimen of camrelizumab combined with paclitaxel and nedaplatin was controllable when used for 2 to 4 neoadjuvant cycles before surgery, but it did not explain whether there were differences in efficacy among different numbers of cycles.

In 2021, a multi-center, Phase II clinical study was carried out in Japan to compare the efficacy and safety of 2 cycles and 3 cycles of neoadjuvant chemotherapy for the treatment of locally advanced ESCC. The results showed that the surgical completion rate and toxicity were similar between the two groups. The ORR of the 3-cycle group was significantly better (42.9% vs. 65.2%, P=0.0027), and the pCR rate was also relatively higher, but there was no significant statistical difference (9.1% vs. 15.3%, P=0.212) (73). A meta-analysis included 15 studies with a total of 452 resectable ESCC patients to compare the efficacy and safety of 2 cycles and > 2 cycles of neoadjuvant treatment. The results showed that the pooled major pathological response (MPR) rate and pathological complete response (PCR) rate of the two groups were 58.3% and 32.9% respectively, the pooled incidences of treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were 91.6% and 19.4% respectively, and the pooled R0 resection rate was 92.8%. Compared with 2 cycles of neoadjuvant treatment, patients who received > 2 cycles of neoadjuvant treatment had higher MPR rates (57.3% vs. 61.1%) and PCR rates (30.6% vs. 37.9%), and higher incidences of TRAEs (89.2% vs. 98.9%), but there was still no significant difference (P > 0.05), and 2 cycles of neoadjuvant treatment showed a higher R0 resection rate (R0 resection rate: 96.0% vs. 87.8%, P=0.02) (67). In addition, in a real-world analysis of neoadjuvant immunotherapy combined with chemotherapy for non-small cell lung cancer, the results showed that extending the neoadjuvant treatment to 3–4 cycles may improve the safety of surgery and reduce the incidence of postoperative complications, but the MPR rate may not increase significantly (57.3% vs. 57.4%, P=0.529) (74). The increase in the number of treatment cycles has not achieved the expected effects in terms of efficacy and safety. In the future, more trials related to the number of treatment cycles of neoadjuvant treatment for locally advanced ESCC are still needed for exploration.

Currently, it is generally recommended clinically that patients with resectable esophageal squamous cell carcinoma (ESCC) undergo surgery 4 to 6 weeks after neoadjuvant chemoradiotherapy (nCRT), but the optimal timing of surgery after neoadjuvant immunotherapy has not been clearly defined.

The SCALE-1 study also reported that 8 patients who underwent surgery within 8 weeks after completing preoperative treatment experienced perioperative complications. After extending this interval to more than 8 weeks, no postoperative complications were found, and a trend of weight gain was observed. This indicates that a longer interval, on the premise of ensuring that it does not increase the complexity of the surgery, may also reduce the incidence of acute toxicity related to neoadjuvant treatment and surgery in patients. In addition, no progression was observed in the intention-to-treat (ITT) population, suggesting that a longer interval will not impair the treatment response.

A retrospective study explored whether the time to surgery (TTS) (> 6 weeks) would affect the outcomes. It included 95 patients with locally advanced ESCC who underwent esophagectomy after neoadjuvant immunotherapy combined with chemotherapy. The primary endpoints were pathological complete response (pCR) and disease-free survival (DFS). The results showed that the pCR rate in the standard group was 23.08% (12/52), and that in the extended group was 16.28% (7/43) (P=0.41). Multivariate regression analysis further indicated that TTS was not an independent factor for predicting pCR (P=0.41). The median follow-up time in the standard TTS group was 10.5 months, and that in the extended TTS group was 11.2 months. A total of 5 recurrences occurred, 2 in the standard TTS group and 3 in the extended TTS group, and there was no significant difference in DFS (P=0.60). Moreover, the complications and major complications in the two groups were similar. Therefore, it is believed that the TTS after neoadjuvant immunotherapy combined with chemotherapy is not important for pathological response, disease-free survival rate, and short-term postoperative outcomes (75). In another retrospective study, the outcomes of patients with locally advanced ESCC who had a time interval between surgery after neoadjuvant immunotherapy combined with chemotherapy of ≤ 8 weeks and > 8 weeks were analyzed. The primary endpoints were DFS and overall survival (OS), and the secondary endpoints were pathological response, surgical outcomes, and postoperative complications. The results showed that there were 44 patients in the ≤ 8 weeks group (n = 44) and 36 patients in the > 8 weeks group (n = 36). The major pathological response (MPR) rates were 25.0% in the ≤ 8 weeks group and 27.8% in the > 8 weeks group (P=0.779). The pCR rates were 11.4% in the ≤ 8 weeks group and 16.7% in the > 8 weeks group (P=0.493). The incidences of postoperative complications were 27.3% in the ≤ 8 weeks group and 19.4% in the > 8 weeks group (P=0.413). The median DFS had not been reached in both groups (hazard ratio [HR]: 3.153, 95% confidence interval [CI] 1.383-6.851, P=0.004). The median OS had not been reached in the ≤ 8 weeks group (HR: 3.703, 95% CI 1.584-8.657; P=0.0012), and it was 31.6 months (95% CI 21.1-42.1) in the > 8 weeks group. In the multivariate analysis, poorer DFS and OS were observed in patients with an interval of > 8 weeks (HR: 2.992, 95% CI 1.306-6.851; HR 3.478, 95% CI 1.481-8.170) (76). Therefore, the choice of the timing of surgery after neoadjuvant immunotherapy combined with chemotherapy is still controversial.

Theoretically, the role of immune checkpoint inhibitors is to release the suppression of T cells and activate the immune system to attack tumors. This process requires time. The initiation, expansion, and eventual manifestation of significant tumor regression or pathological response (such as pCR/MPR) are usually not immediate. Clinically and radiologically significant responses may not appear until several weeks or even months after treatment. Premature surgery may interrupt an ongoing effective immune response and miss the opportunity to achieve deeper pathological remission. However, considering that an excessively long interval could lead to the risk of disease progression, we believe that 6 to 8 weeks after neoadjuvant immunotherapy may be the optimal surgical window. Further prospective clinical studies are still needed in the future to verify this.

Currently, in clinical practice, patients who have not achieved R0 resection, pCR, or who are found to have lymph node metastasis intraoperatively and are at high risk of recurrence usually undergo adjuvant immunotherapy, which is often initiated within 3 months after surgery; otherwise, the therapeutic efficacy may be reduced, and the risk of recurrence may increase. However, in recent years, there has been ongoing debate regarding the optimal population for adjuvant immunotherapy after esophageal cancer surgery, the best treatment regimen, and even whether adjuvant immunotherapy is necessary at all after surgery.There are differences in the mechanisms of action between adjuvant immunotherapy and neoadjuvant immunotherapy: Neoadjuvant therapy focuses on tumor debulking, so immunotherapy primarily works by reducing T cell-mediated immunosuppression. In adjuvant therapy, after tumor resection, the goal of immunotherapy is to eliminate potential micrometastases that may exist but are undetectable by standard diagnostic tests. Therefore, its mechanism is more likely to involve activating T lymphocytes to clear micrometastases (77). However, after surgical resection, the release of antigens is reduced, and the immune system lacks continuous stimulation, making it difficult to elicit a robust T-cell response. Moreover, lymphadenectomy during surgery can damage the lymphatic system surrounding the tumor bed, further weakening the efficiency of immune cell migration and activation. Therefore, the application of immunotherapy in the neoadjuvant setting is likely to offer more clinical benefits. This conclusion has been validated in mouse animal models, clinical studies, and large-scale informatics studies (78–80).

Given this, some patients may opt for more aggressive adjuvant treatment regimens after surgery, such as immunotherapy combined with chemotherapy or chemoradiotherapy. The overall mechanism of action of adjuvant immunotherapy combined with chemotherapy or radiotherapy includes the unique and crucial effects brought about by chemotherapy or radiotherapy, especially the induction of immunogenic cell death, alteration of the tumor microenvironment, and massive release of antigens. These mechanisms synergize with immunotherapy, significantly differing from the mode of action of immunotherapy alone. Therefore, theoretically, the combination of immunotherapy with chemotherapy or radiotherapy should provide better tumor-killing effects. However, there is currently a lack of research results comparing the long-term survival outcomes of these two approaches.

In addition, the issue of acquired resistance is also evident in adjuvant immunotherapy after surgery. Residual micrometastases after surgery are often accompanied by fibrotic stromal proliferation and high expression of TGF-β, creating a suppressive environment that hinders T-cell infiltration. A recent study retrospectively analyzed data from seven years across eight centers in China, involving a total of 1,428 patients with locally advanced ESCC. The results indicated that whether patients received adjuvant immunotherapy after surgery did not affect OS and DFS (P=0.35) (81). Therefore, adjuvant immunotherapy currently faces many limitations and challenges. Relevant prospective Phase III clinical studies are ongoing ( Table 2 ), and we look forward to the publication of the study results, which will provide more theoretical basis for adjuvant immunotherapy.

On the other hand, a real-world analysis of adjuvant treatment after esophageal cancer surgery was conducted in the form of a retrospective cohort study. The immunotherapy cohort was evaluated in terms of treatment completion, adverse reactions, and disease progression, with a focus on patients who underwent surgery in 2021 and their eligibility for receiving nivolumab. The results showed that 39 patients received immunotherapy, while 137 patients did not receive immunotherapy. In the logistic regression analysis, after adjusting for age and receipt of adjuvant chemoradiotherapy, no statistically significant effect of immunotherapy on the 1-year overall survival rate was found. Among the 39 patients who received immunotherapy, only 7 patients successfully completed the treatment (18%), and most of the patients failed due to disease progression or side effects. Among the 39 patients who received immunotherapy, 19 received nivolumab, 17 received pembrolizumab, 11 received trastuzumab, and 2 received ipilimumab. Among the 17 patients who were eligible for nivolumab treatment, 13 patients received nivolumab treatment (76.4%), and 3 patients completed the entire course of treatment (82). Therefore, although adjuvant immunotherapy holds promise for improving the survival of patients with esophageal cancer, the practice in real life differs greatly from that in clinical trials, and most patients are unable to complete the immunotherapy regimen. This will also be one of the challenges faced by adjuvant treatment after esophageal cancer surgery in the future.

Currently, comprehensive treatment mainly based on surgery is the main treatment strategy for patients with early-stage and locally advanced resectable esophageal cancer. However, esophageal cancer surgery has a relatively large trauma and has a great impact on the quality of life of patients. In addition, for locally advanced resectable esophageal cancer, although neoadjuvant chemoradiotherapy is one of the current standard treatment regimens, there has always been a controversy about whether surgical resection is still necessary after achieving a clinical complete response (cCR) following neoadjuvant chemoradiotherapy. In recent years, with the publication of the results of the Dutch pre-SANO trial, “organ preservation” treatment for esophageal cancer has become a hot topic worldwide. The pre-SANO study explored methods for evaluating the clinical response to detect local residual lesions, including endoscopic ultrasound, bite biopsy, and fine-needle aspiration of suspicious lymph nodes, after neoadjuvant chemoradiotherapy for esophageal cancer. PET-CT was used to detect tumor recurrence and metastasis. It preliminarily established the feasibility of the “wait and see” strategy for organ preservation in esophageal cancer and provided a reference for the subsequent phase 3 randomized controlled SANO trial (83). The SANO study divided patients who achieved cCR after neoadjuvant chemoradiotherapy into two groups. One group received SS (standard surgery), and the other group received AS (active surveillance). The primary endpoint of the study was overall survival (OS). The preliminary results of the SANO study were announced at the ESMO conference in 2023. There were 198 patients in the AS group (active surveillance group) and 111 patients in the SS group (standard surgery group). The results showed that 83 patients in the AS group underwent surgery after tumor recurrence, with a median time to surgery of 5.9 months. The complications of the surgical patients in the AS group and the SS group were similar. 35% of the patients in the AS group had a durable response, and 48% of the patients had recurrence. At least 35% of the patients avoided unnecessary surgery due to AS. The 2-year follow-up showed that the primary endpoint was non-inferior, and there were no statistically significant differences in OS and disease-free survival (DFS) (84). Overall, the SANO study provides a key reference for the future organ preservation treatment strategy of esophageal cancer. After that, the pre-SINO study led by Chinese researchers explored for the first time the correlation between changes in circulating tumor DNA (ctDNA) combined with clinical modular examination and pathological outcomes after neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC). ctDNA, detected through tumor DNA fragments in the blood, has high sensitivity and specificity, which can increase accuracy and reduce the false negative rate of cCR patients. The pre-SINO study reported the latest research results at the 2022 ASCO conference. The false negative rate of ctDNA liquid biopsy was only 5%, which was better than the 10% false negative rate in the SANO study (85, 86). It effectively reduced the incidence of clinical misassessment of non-pCR patients, especially bringing a cure opportunity for patients who may miss the surgery in the future due to misassessment as cCR. It suggests that ctDNA liquid biopsy may become an effective active monitoring strategy for the management of ESCC in the future. The treatment regimens of the SANO and SINO series of studies are both concurrent chemoradiotherapy (CROSS regimen). In the context of the immunotherapy era, the combination of immunotherapy and concurrent chemoradiotherapy will enable more patients to achieve a clinical complete response. Theoretically, these patients may not need to undergo surgery and can preserve the esophageal organ. Therefore, the combination of immunotherapy with chemoradiotherapy or the combination of immunotherapy with chemotherapy as a treatment regimen for organ preservation in ESCC patients will be one of the future research focuses. The IKF-t057/PRESTO announced by ASCO-GI is a single-arm phase II study design of the organ preservation strategy for esophageal adenocarcinoma using the combination of immunotherapy with chemoradiotherapy. The study plans to enroll 32 patients with resectable T1-2N0M0 esophageal adenocarcinoma (including adenocarcinoma of the gastroesophageal junction). The enrolled patients will receive durvalumab (once every 4 weeks) and 2 cycles of FLOT (once every 2 weeks) induction therapy simultaneously, followed by 3 cycles of mFOLFOX (once every 2 weeks) and concurrent radiotherapy. The patients will be evaluated 8 weeks after treatment. Patients with confirmed local tumor residue will undergo surgical resection, and patients who achieve cCR will enter the maintenance treatment stage, continuing to receive single-agent durvalumab treatment for up to 12 cycles, and will be regularly examined and re-evaluated. The primary endpoint is the cCR rate/pCR rate at re-evaluation. If the cCR rate/pCR rate ≥ 75%, the treatment regimen will be further studied, while if it is < 55%, no further study is required (87). The first patient was enrolled in August 2023, and the recruitment is still ongoing. It is expected to be completed in August 2024, and we are looking forward to the announcement of the results.