Keqiang Chen

Autoimmune diseases, immune-mediated inflammatory diseases, and cancer are distinct pathological conditions that can intersect through immune dysregulation, chronic inflammation, impaired host defense, and altered host–microbe interactions. In selected settings, autoimmune and immune-mediated inflammatory diseases are associated with increased gastrointestinal cancer risk. Although bacterial and viral contributions to inflammation-associated cancer have been extensively studied, the role of fungi remains less investigated. This Opinion article discusses host–fungus interactions through two experimental mouse models that connect altered immune tolerance, innate antifungal responses, and gastrointestinal tumorigenesis. Kinase-dead IKKα K44A knock-in mice develop defective central immune tolerance, APECED-like autoimmune manifestations, mucosal fungal infection, epithelial EGFR signaling, and esophageal squamous cell carcinoma. By contrast, Card9^−/− mice provide a distinct model in which impaired innate antifungal immunity alters intestinal fungal ecology and myeloid-cell responses in colitis-associated colorectal cancer. In the CARD9 setting, fungi may exert pathogenic or protective effects depending on host genotype, immune context, fungal species, and mycobiome structure. Together, these models provide useful tools for investigating how fungi may contribute to gastrointestinal tumorigenesis through cancer-promoting inflammation and immune suppression in a context-dependent manner. However, these findings do not yet validate clinical strategies and should not be interpreted as broadly representative of all autoimmune or immune-mediated inflammatory diseases. Further mechanistic and human studies are needed.

The discovery of immune checkpoint proteins has marked a major breakthrough in cancer immunotherapy. During cancer development and progression, tumor cells exploit multiple immune checkpoint pathways to evade immune surveillance. Immune checkpoint inhibitors (ICIs) have been developed to restore antitumor immunity by reactivating immune cells that are functionally suppressed within the tumor microenvironment. This review provides a comprehensive overview of the regulation and therapeutic targeting of immune checkpoint proteins in cancer, covering both classical checkpoints, including PD-1, PD-L1, and CTLA-4, and emerging targets such as LAG-3, TIM-3, TIGIT, BTLA, SIRP-α, CD200, ILT4, and CD24. In addition, we summarize current clinical advances and the therapeutic potential of approved and investigational ICIs, examine the mechanisms underlying ICI resistance, and discuss future strategies to overcome resistance, highlighting the mechanisms of action and their implications for future cancer treatment.

Background: Formyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. Commensal E. coli is known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection between E. coli and Fpr2 in the recovery of colon epithelial cells. Results: The deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes of E. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing. E. coli O22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated with E. coli O22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection with E. coli O22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived from E. coli O22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population of E. coli was observed to increase in the colons of Fpr2^−/− mice with colitis. Conclusion: Commensal E. coli O22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products from E. coli induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increased E. coli population in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensal E. coli on colon epithelial cell recovery.

Human cathelicidin antimicrobial peptide LL-37 (LL-37) is an antimicrobial peptide derived from its precursor protein hCAP18, which is an only cathelicidin in human. LL-37 not only serves as a mediator of innate immune defense against invading microorganisms, but it also plays an essential role in tissue homeostasis, regenerative processes, regulation of proinflammatory responses, and inhibition of cancer progression. Therefore, LL-37 has been considered as a drug lead for diseases. However, high levels of LL-37 may reduce cell viability and promote apoptosis of osteoblasts, vascular smooth muscle cells, periodontal ligament cells, neutrophils, airway epithelial cells and T cells. Recent evidence reveals that LL-37-derived short peptides possess similar biological activities as the whole LL-37 with reduced cytotoxicity. Thus, such small molecules constitute a pool of potential therapeutic agents for diseases.

Mouse cathelin-related antimicrobial peptide (CRAMP) and its homologue human cathelicidin (LL-37) play active roles in innate immune responses, angiogenesis, and wound healing. In addition, LL-37/CRAMP fends off microbes and protects against infections in the colon, where the epithelium is exposed to myriad of enteric pathogens. It is increasingly recognized that LL-37/CRAMP maintains colon mucosal barrier integrity, shapes the composition of microbiota, and protects the host from tumorigenesis. In this review, we discuss the importance of LL-37/CRAMP in the homeostasis of the host, with novel findings derived from mice deficient in CRAMP that support the proposition for this natural antimicrobial peptide and an immune modulator as a drug lead for therapeutic development.

In proliferative diabetic retinopathy (PDR), activated Müller glial cells (MGCs) exhibit increased motility and a fibroblast-like proliferation phenotype that contribute to the formation of fibrovascular membrane. In this study, we investigated the capacity of high glucose (HG) to regulate the expression of cell surface receptors that may participate in the proinflammatory responses of MGCs. We found that MGCs express a G-protein coupled chemoattractant receptor formyl peptide receptor 2 (Fpr2) and fibroblast growth factor receptor 1 (FGFR1), which mediated MGC migration and proliferation in response to corresponding ligands. HG upregulated Fpr2 through an NF-κB pathway in MGCs, increased the activation of MAPKs coupled to Fpr2 and FGFR1, which also further enhanced the production of vascular endothelial growth factor by MGCs in the presence of HG. In vivo, Fpr2 was more highly expressed by retina MGCs of diabetic mice and the human counterpart FPR2 was detected in the retina MGCs in fibrovascular membrane of PDR patients. To support the potential pathological relevance of Fpr2, an endogenous Fpr2 agonist cathelin-related antimicrobial peptide was detected in mouse MGCs and the retina, which was upregulated by HG. These results suggest that Fpr2, together with FGFR1, may actively participate in the pathogenesis of PDR thus may be considered as one of the potential therapeutic targets.