Nectin2, also known as PVRL2, belongs to the immunoglobulin superfamily. It plays a role in cell-to-cell adhesion, being involved in the establishment of adherens and tight junctions. It is also a ligand for the activating receptor CD226, contributing to cytotoxic lymphocyte-mediated recognition and killing of damaged cells. Its expression is regulated by the ubiquitin-proteasome pathway [6].

In neuroblastoma, Nectin2 is of great significance. Serum Nectin2 level is increased in NB patients, correlated with INSS classification and shorter overall survival. Knockdown of Nectin2 reduces cell migration, induces apoptosis and cell cycle arrest, and affects the expression of genes like ANXA2 [3]. In addition, single-cell RNA sequencing analysis of neuroblastomas identified the NECTIN2-TIGIT axis as a crucial immune checkpoint. Blockade of TIGIT and PD-L1 together significantly reduces neuroblastoma growth in vivo [1].

In colorectal cancer, a new cluster of cancer-associated fibroblasts named "T cell-inhibiting CAF" characterized by Nectin2 expression can inhibit effector T cells via Nectin2 signaling, and Nectin2 expression is a poor prognostic factor [2].

In lung adenocarcinoma, high Nectin2 expression is associated with reduced overall survival and lower recurrence-free survival. Nectin2 knockout promotes cell apoptosis and diminishes cell proliferation and migration capacity [4].

In pancreatic ductal adenocarcinoma, tumor-associated neutrophils upregulate Nectin2 expression, creating an immunosuppressive microenvironment, and blocking Nectin2 improves CD8+ T-cell function and suppresses tumor progression [5].

In conclusion, Nectin2 is involved in multiple biological processes related to cancer, including cell adhesion, apoptosis, immune regulation, and metastasis. Studies using gene knockdown (akin to loss-of-function experiments) in various cancer cell lines and in vivo models have revealed its role in promoting tumor progression and immunosuppression in diseases such as neuroblastoma, colorectal cancer, lung adenocarcinoma, and pancreatic ductal adenocarcinoma. These findings suggest Nectin2 as a potential therapeutic target for these cancers.