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Colorectal cancer (CRC) is considered as a global major cause of cancer death. Surgical resection is the main line of treatment; however, chemo-, radiotherapy and other adjuvant agents are crucial to achieve good outcomes. The tumor microenvironment (TME) is a well-recognized key player in CRC progression, yet the processes linking the cancer cells to its TME are not fully delineated. Autophagy is one of such processes, with a controversial role in the pathogenesis of CRC, with its intricate links to many pathological factors and processes. Autophagy may apparently play conflicting roles in carcinogenesis, but the precise mechanisms determining the overall direction of the process seem to depend on the context. Additionally, it has been established that autophagy has a remarkable effect on the endothelial cells in the TME, the key substrate for angiogenesis that supports tumor metastasis. Favorable response to immunotherapy occurs only in a specific subpopulation of CRC patients, namely the microsatellite instability-high (MSI-H). In view of such limitations of immunotherapy in CRC, modulation of autophagy represents a potential adjuvant strategy to enhance the effect of those relatively safe agents on wider CRC molecular subtypes. In this review, we discussed the molecular control of autophagy in CRC and how autophagy affects different processes and mechanisms that shape the TME. We explored how autophagy contributes to CRC initiation and progression, and how it interacts with tumor immunity, hypoxia, and oxidative stress. The crosstalk between autophagy and the TME in CRC was extensively dissected. Finally, we reported the clinical efforts and challenges in combining autophagy modulators with various cancer-targeted agents to improve CRC patients’ survival and restrain cancer growth.

Previous work has shown that reduced expression of PLCXD3, a member of the phosphoinositide-specific phospholipases (PI-PLC) family, impaired insulin secretion with an unclear mechanism. In the current study, we aim to investigate the mechanism underlying this effect using human islets and rat INS-1 (832/13) cells. Microarray and RNA sequencing data showed that PLCXD3 is among the highly expressed PI-PLCs in human islets and INS-1 (832/13) cells. Expression of PLCXD3 was reduced in human diabetic islets, correlated positively with Insulin and GLP1R expression and inversely with the donor's body mass index (BMI) and glycated hemoglobin (HbA1c). Expression silencing of PLCXD3 in INS-1 (832/13) cells was found to reduce glucose-stimulated insulin secretion (GSIS) and insulin content. In addition, the expression of Insulin, NEUROD1, GLUT2, GCK, INSR, IRS2, and AKT was downregulated. Cell viability and apoptosis rate were unaffected. In conclusion, our data suggest that low expression of PLCXD3 in pancreatic β-cells associates with downregulation of the key insulin signaling and insulin biosynthesis genes as well as reduction in glucose sensing.