TSPAN6, a tetraspanin protein, has diverse functions. It can interact with multiple molecules and is involved in various signaling pathways, playing important roles in cell-cell communication, immune response, and tumor-related processes [1,2,3,4,5,6]. It participates in pathways such as the EGFR-RAS pathway, STAT3 signaling pathway, and retinoic acid-inducible gene I-like receptor-mediated immune signaling pathway [1,2,6].

In Ras-driven cancers, whole-body knockout as well as tumor cell autonomous inactivation using floxed alleles of Tspan6 in mice enhanced KrasG12D-driven lung tumor initiation and malignant progression. TSPAN6 binds to the EGFR and blocks EGFR-induced RAS activation, thus suppressing tumor growth and metastatic dissemination of human RAS-activating mutant pancreatic cancer xenografts [1].

In glioblastoma, TSPAN6 promoted the malignant progression of glioblastoma via promoting the proliferation and metastatic potential of glioblastoma cells, and it enhanced angiogenesis via regulating the tumor microenvironment (TME) and STAT3 signaling pathway [2].

In breast cancer, Tspan6 stimulates the chemoattractive potential of breast cancer cells for B cells in an extracellular vesicle (EV)-and Liver X receptor (LXR)-dependent manner, which controls the immune microenvironment [3].

In adipose-derived stem cells (ADSCs), TSPAN6 stimulates exosome secretion and formation, as well as the creation of multivesicular bodies (MVBs) and intraluminal vesicles (ILVs), and ADSCsTSPAN6 +-Exos has a greater ability to support wound healing, angiogenesis, and the proliferation and migration of a variety of cells [4].

In glioma, TSPAN6 expression was significantly upregulated, and its downregulation inhibited U251 cell proliferation, disrupted the cell cycle, diminished migratory capabilities, and reduced the recruitment of macrophages [5]. Also, TSPAN6 negatively regulates retinoic acid-inducible gene I-like receptor-mediated immune signaling in a ubiquitination-dependent manner [6].

In conclusion, TSPAN6 has a wide-ranging impact on multiple biological processes and diseases. Gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its significance in Ras-driven cancers, glioblastoma, breast cancer, wound healing, and immune response regulation. These findings help in understanding the biological functions of TSPAN6 and provide potential therapeutic targets for related diseases.