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For colorectal cancer (CRC), surgical resection remains essential for achieving good prognoses. Unfortunately, numerous patients with locally advanced CRC and metastatic CRC failed to meet surgical indications or achieve pathological complete response after surgery. Perioperative therapy has been proven to effectively lower tumor staging and reduce recurrence and metastasis. Immune checkpoint inhibitors (ICIs) have shown unprecedented prolongation of survival time and satisfactory safety in patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR), while the therapeutic effect obtained by patients with mismatch repair-proficient or microsatellite stable (pMMR/MSS) was considered minimal. However, recent studies found that certain CRC patients with dMMR/MSI-H presented intrinsic or acquired immune resistance, and pMMR/MSS CRC patients can also achieve better efficacy. Therefore, more predictors are required for screening patients with potential clinical benefits. Since the discovery of synergistic effects between immunotherapy, chemotherapy, and radiotherapy, different immunotherapy-based therapies have been applied to the perioperative therapy of CRC in an increasing number of research. This review comprehensively summarized the past and current progress of different combinations of immunotherapy in perioperative clinical trials for CRC, focusing on the efficacy and safety, and points out the direction for future development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Zhou, Han, Wei and Qiu.)

Objective: To assess the clinical efficacy of neoadjuvant chemoradiotherapy combined with immunotherapy for patients with microsatellite stable (MSS) locally advanced rectal cancer and provide evidence to support clinical decision-making., Methods: A systematic search was conducted on the PubMed, Embase, Cochrane Collaboration databases, conference summaries, and Chinese databases for clinical studies that investigated neoadjuvant chemoradiotherapy combined with immunotherapy for the treatment of locally advanced rectal cancer with MSS status. The search spanned from the inception of each database through July 2023. Data from the identified studies were extracted using a pre-designed table, and efficacy outcomes were analyzed. An integrated analysis was conducted using Stata 12.0 software., Results: Eight studies were included, comprising 204 patients with locally advanced MSS rectal cancer who received chemoradiotherapy combined with immunotherapy. The integrated analysis revealed a pathologic complete remission rate of 0.33, a sphincter preservation rate of 0.86, an R0 resection rate of 0.83, a major pathologic remission rate of 0.33, and a clinical complete remission rate of 0.30., Conclusion: Neoadjuvant chemoradiotherapy combined with immunotherapy demonstrates significant short-term efficacy in MSS-type locally advanced rectal cancer, notably enhancing the pathologic complete remission and sphincter preservation rates. This combination is a recommended treatment for patients with MSS-type rectal cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yue, Cheng, Xi, Wang, Wei and Zheng.)

Background: Microsatellite stable (MSS) colorectal cancer (CRC) has been referred to as the "cold tumor" because of almost no response to anti-programmed death-1 (PD-1) antibody. A recent REGONIVO trial showed that regorafenib plus nivolumab had an encouraging efficacy in MSS metastatic CRC (mCRC). However, only a small subset of patients may benefit from the combination therapy. We aim to evaluate the efficacy and safety data of immune checkpoint inhibitors combined with regorafenib in refractory MSS mCRC and to discover biomarkers that can effectively stratify the beneficial patient population., Methods: We retrospectively analyzed patients with MSS mCRC who received regorafenib combined with anti-PD-1 antibody therapy. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and status of gene mutation were reviewed and evaluated., Results: Twenty-one patients received combination treatment. At a median treatment duration of 4 months, one patient achieved complete response, three patients achieved partial response, and two patients achieved stable disease as the best response. The ORR and DCR were 19% and 28.5% in the overall population, respectively. The median PFS was 4 months, and the median OS was 25 months. Only erbb2 receptor tyrosine kinase 2/erbb3 receptor tyrosine kinase 3 (ERBB2/ERBB3) mutation status was confirmed to be a potential predictive factor for effective treatment. In patients with ERBB2/ERBB3 mutation, ORR, DCR, and PFS exhibited significant improvements in comparison with that in wild-type patients. Grade 3 or higher treatment-related adverse events occurred in three patients (14.3%)., Conclusions: Regorafenib in combination with PD-1 inhibitor provides a feasible treatment regimen for refractory MSS mCRC with tolerated toxicity. Patients with ERBB2/ERBB3 mutation may be the preferred population for this combination regimen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dai, Ding, He, Huang, Liu and Wu.)

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator., Competing Interests: SS declares speaker fees from AMGEN, SERVIER, MERCK, MSD, travel/accomodation and expenses from NOVARTIS, IPSEN, AMGEN, TRIPLA-A, PFIZER, CELLGENE, and they’re a member of a roundtable for ASTRAZENECA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gandini, Puglisi, Pirrone, Martelli, Catalano, Nardin, Seeber, Puccini and Sciallero.)

Objectives: The antitumor activity of nivolumab plus regorafenib in colorectal cancer from a phase Ib REGONIVO study is encouraging. The present study was conducted to evaluate the efficacy and safety of regorafenib or fruquintinib plus sintilimab as third-line or above therapy in patients with microsatellite stable (MSS) metastatic colorectal cancer., Methods: Patients with MSS metastatic colorectal cancer who have failed from prior treatment and received regorafenib or fruquintinib plus sintilimab as third-line or above therapy from January 2019 to December 2020 were prospectively analyzed based on real-world clinical practice. The primary end point was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety., Results: 42 patients received regorafenib plus sintilimab(RS), and the other 30 patients received fruquintinib plus sintilimab(FS). In the general population, the ORR and DCR were 13.9% and 70.8%, and the median PFS and OS was 4.2(95% CI=2.9-5.5) and 10.5 (95% CI=8.6-12.4) months, respectively. There were no statistically significant differences between RS and FS group in PFS (3.5(2.2-4.8) vs. 5.5(3.5-7.5) months, P=0.434) and OS (11.0(7.0-15.0) vs. 10.5(3.8-17.2) months, P=0.486). Subgroup analysis suggested that patients without liver metastasis responded well to this combination regimen (ORR: 21.4% vs. 9.1%) and obtained better OS (26(8.8-43.2) vs. 10.0(7.4-12.6) months, P=0.016). The incidence of Grade 3-4 adverse events (AEs) was 15.3% and the toxicities were generally tolerable and manageable., Conclusions: Regorafenib or fruquintinib plus sintilimab as third-line or above therapy provide a feasible treatment regimen for MSS metastatic colorectal cancer with tolerated toxicity. Patients without liver metastasis may be the preferred population for this combination regimen., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nie, Lv, Chen, Xu, Wang, Liu, Wang, Zhao, He and Chen.)

Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated deaths worldwide. Patients with microsatellite instability-high (MSI-H) tumors were shown to highly benefit from immune checkpoint inhibitors (ICIs) than patients with microsatellite stable (MSS) tumors. Furthermore, the infiltration of immune cells and the expression of cancer stem cells (CSCs) in COAD were associated with the anti-tumor immune response. However, the potential mechanisms showing the relationship between microsatellite instability and CSCs or tumor-infiltrating immune cells (TIICs) have not been elucidated. Accumulating evidence reveals that achaete-scute family bHLH transcription factor 2 (ASCL2) plays a crucial role in the initiation and progression of COAD and drug resistance. However, the specific biological functions of ASCL2 in COAD remain unknown. In this study, we performed weighted gene co-expression network analysis (WGCNA) between MSS and MSI-H subsets of COAD. The results revealed that ASCL2 was a potential key candidate in COAD. Subsequently, the single-cell RNA-seq revealed that ASCL2 was positively associated with CSCs. Further, ASCL2 was shown to indirectly affect tumor immune cell infiltration by negatively regulating the expression of DUSP4. Finally, we inferred that the immunotherapy-sensitive role of ASCL2/DUSP4 axis on COAD is partly attributed to the activation of WNT/β-catenin pathway. In conclusion, this study revealed that ASCL2 was positively correlated to CSCs and tumor immune infiltration in COAD. Therefore, ASCL2 is a promising predictor of clinical responsiveness to anti-PD-1/PD-L1 therapy in COAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Sun, Qu, Liu, Sun, Pan, Zheng and Su.)

Background: For a majority of patients with metastatic colorectal cancer (mCRC) with MS stable (MSS) or mismatch repair proficient (pMMR), the role of immunotherapy is undetermined. This study investigated the efficacy and safety of camrelizumab when added to XELOX chemotherapy plus bevacizumab or regorafenib as first-line therapy for mCRC., Materials and Methods: Medical records of mCRC patients who received camrelizumab and XELOX plus bevacizumab or regorafenib at the First Hospital of Quanzhou Affiliated to Fujian Medical University between June 1, 2019, and April 30, 2021, were retrospectively collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed., Results: Twenty-five eligible patients received combination therapy, including bevacizumab in 19 patients and regorafenib in 6. Twenty-one patients had pMMR/MSS and one MSI-H. Of the 25 patients who could be evaluated for efficacy, 18 (72%) achieved PR, 6 (24%) achieved SD, and 1 (4%) achieved PD. The ORR and DCR were 72% (18/25) and 96% (24/25), respectively. The median progression-free survival (PFS) was 11.2 months (95% CI 8.9-13.9), and OS had not yet been reached. The combination regimen of regorafenib in six (24%) patients was unassociated with treatment outcomes. Most AEs were either grade 1 or 2, and treatment-related grade 3 toxicities were observed in 8/25 (32%) patients., Conclusion: Camrelizumab combined with XELOX plus bevacizumab or regorafenib was feasible, producing high rates of responses as first-line therapy in unselected Chinese patients with MSS mCRC. The toxicities were generally tolerable and manageable. Prospective randomized trials with large sample sizes are needed to evaluate these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Wang, Lin, Cai, Li and He.)

Background: Microsatellite stability (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. Studies have shown that antiangiogenic drugs combined with programmed death receptor-1 (PD-1) inhibitors can improve immunosuppression. The purpose of this study was to compare the efficacy of fruquintinib combined with PD-1 inhibitor (FP) and regorafenib combined with PD-1 inhibitor (RP) in the treatment of advanced mCRC with MSS or pMMR., Materials and Methods: We retrospectively collected advanced MSS or pMMR mCRC patient data from The Second Affiliated Hospital of Nanchang, China, from June 2019 to March 2021. Then, we analyzed and compared the efficacy and safety of FP and RP., Results: A total of 51 patients who met the criteria were divided into FP (n = 28) and RP groups (n = 23). The overall response rate of the FP and RP groups was 7.1% and 8.7% and the disease control rate was 89.3% and 56.5%, respectively. The median progression-free survival (PFS) time was higher in the FP group than in the RP group (6.4 vs. 3.9 months, respectively; P = 0.0209). Patients with no liver metastasis, KRAS wild type, and left colon tumor may benefit from FP. Eight patients (15.7%) had grade 3 toxicity related to treatment. Cox multivariate regression analysis showed that the treatment method was an independent risk factor for median PFS time., Conclusion: Our study indicates that FP could improve PFS time of patients with advanced mCRC compared with RP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sun, Huang, Li, Mao, Wang and Wu.)

Background: Microsatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs., Materials and Methods: We retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China., Results: Twenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients., Conclusion: No objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration., (Copyright © 2020 Li, Cong, Liu, Peng, Wang, Feng, Yue, Li, Wang and Wang.)