Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability—high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.

Liver metastasis of colorectal cancer (CRLM) is the most common cause of CRC‐related mortality, and is typically caused by interactions between CRC cells and the tumour microenvironment (TME) in the liver. However, the molecular mechanisms underlying the crosstalk between tumour‐derived extracellular vesicle (EV) miRNAs and the TME in CRLM have yet to be fully elucidated. The present study demonstrated that highly metastatic CRC cells released more miR‐181a‐5p‐rich EVs than cells which exhibit a low metastatic potential, in‐turn promoting CRLM. Additionally, we verified that FUS mediated packaging of miR‐181a‐5p into CRC EVs, which in‐turn persistently activated hepatic stellate cells (HSCs) by targeting SOCS3 and activating the IL6/STAT3 signalling pathway. Activated HSCs could secrete the chemokine CCL20 and further activate a CCL20/CCR6/ERK1/2/Elk‐1/miR‐181a‐5p positive feedback loop, resulting in reprogramming of the TME and the formation of pre‐metastatic niches in CRLM. Clinically, high levels of serum EV containing miR‐181a‐5p was positively correlated with liver metastasis in CRC patients. Taken together, highly metastatic CRC cells‐derived EVs rich in miR‐181a‐5p could activate HSCs and remodel the TME, thereby facilitating liver metastasis in CRC patients. These results provide novel insight into the mechanism underlying liver metastasis in CRC.

Background: Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods: Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results: In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion: In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

Background: Circular RNAs (circRNAs) generated by back‐splicing of precursor mRNAs (pre‐mRNAs) are often aberrantly expressed in cancer cells. Accumulating evidence has revealed that circRNAs play a critical role in the progression of several cancers, including colorectal cancer (CRC). However, the current understandings of the emerging functions of circRNAs in CRC lipid metabolism and the underlying molecular mechanisms are still limited. Here, we aimed to explore the role of circCAPRIN1 in regulating CRC lipid metabolism and tumorigenesis. Methods: circRNA microarray was performed with three pairs of tumor and non‐tumor tissues from CRC patients. The expression of circRNAs were determined by quantitative PCR (qPCR) and in situ hybridization (ISH). The endogenous levels of circRNAs in CRC cells were manipulated by transfection with lentiviruses overexpressing or silencing circRNAs. The regulatory roles of circRNAs in the occurrence of CRC were investigated both in vitro and in vivo using gene expression array, RNA pull‐down/mass spectrometry, RNA immunoprecipitation assay, luciferase reporter assay, chromatin immunoprecipitation analysis, and fluorescence in situ hybridization (FISH). Results: Among circRNAs, circCAPRIN1 was most significantly upregulated in CRC tissue specimens. circCAPRIN1 expression was positively correlated with the clinical stage and unfavorable prognosis of CRC patients. Downregulation of circCAPRIN1 suppressed proliferation, migration, and epithelial‐mesenchymal transition of CRC cells, while circCAPRIN1 overexpression had opposite effects. RNA sequencing and gene ontology analysis indicated that circCAPRIN1 upregulated the expressions of genes involved in CRC lipid metabolism. Moreover, circCAPRIN1 promoted lipid synthesis by enhancing Acetyl‐CoA carboxylase 1 (ACC1) expression. Further mechanistic assays demonstrated that circCAPRIN1 directly bound signal transducer and activator of transcription 2 (STAT2) to activate ACC1 transcription, thus regulating lipid metabolism and facilitating CRC tumorigenesis. Conclusions: These findings revealed the oncogenic role and mechanism of circCAPRIN1 in CRC. circCAPRIN1 interacted with STAT2 to promote CRC tumor progression and lipid synthesis by enhancing the expression of ACC1. circCAPRIN1 may be considered as a novel potential diagnostic and therapeutic target for CRC patients.

BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measured CAFs in vivo using the ⁶⁸Ga-labeled fibroblast activation protein inhibitor-04 (⁶⁸Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-β inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent ⁶⁸Ga-FAPI and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT imaging. The relationship between uptake of ⁶⁸Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-βR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by ⁶⁸Ga-FAPI and ¹⁸F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptake rates of ⁶⁸Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-βR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. ⁶⁸Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-βR inhibitor with immunotherapy. CONCLUSION. ⁶⁸Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of ⁶⁸Ga-FAPI PET/CT to guide precise TGF-β inhibition plus immunotherapy in CRC patients, recommending ⁶⁸Ga-FAPI and ¹⁸F-FDG dual PET/CT for CRC management. TRIAL REGISTRATION. CFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry. FUNDING. National Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).