Overall, through an in vitro investigation of PANX1 deletion and channel blocking, an in vivo characterization of a chemical carcinoma model in Panx3 KO mice and an analysis of patient‐derived tissue, we observed that PANX1 and PANX3 dysregulation may have potential tumour‐promoting or tumour‐suppressive effects for keratinocyte transformation into cSCC, respectively. Here, PANX3 is linked to carcinoma.