Here, we integrated analyses of patients with cancer from The Cancer Genome Atlas (TCGA) cohort and newly established mouse preclinical anti–PD-1 therapy–refractory models (CT26 P3 or YUMM2.1 P3) and found that elevated NANOG expression in tumors could reprogram the tumor microenvironment (TME) into one that was immunologically nonresponsive to tumors. Here, NANOG is linked to neoplasm.