Natural Killer (NK) cells are cytotoxic innate lymphocytes that specialize in recognizing and eliminating altered cells via a myriad of strategies that can interrupt cancer growth and spread. However, NK cell function and cytotoxicity can be dysregulated by the surrounding tumor microenvironment (TME) in solid tumors. Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that is released into the TME upon cancer progression and metastasis and can promote local inflammation by activation of its receptors (TNFR) 1 or 2 that are differentially expressed across immune and non-immune cells¹. During S. Typhimurium infection, we observed TNFR1 playing a role in accelerating cell death, while TNFR2 promoted NK effector functions². However, the roles of these receptors on NK cell anti-tumor capacities are still poorly understood. To investigate this, transgenic mice models with conditional deletion of TNFRs in NK cells were used to assess how TNF signaling via its receptors influences NK cell-mediated tumor surveillance. Functional and phenotypic changes of TME-infiltrating NK cells were also characterized via high dimensional flow cytometry. We observed that Tnfr1 deficiency decreased NK cell killing capacity in vitro and increased lung metastasis in vivo in a B16F10 mouse model of melanoma. Additionally, transcriptomic and flow cytometry approaches were utilized to investigate the differential effects of TNFR1 and TNFR2 in human NK cells via stimulation with TNFR1- and TNFR2-specific agonists. TNFR2 stimulation promoted NK cell proliferation and activation by upregulating Ki-67, CD69 and Tim3 but reduced granzyme B production. Deciphering the distinct roles of TNFR1 and TNFR2 on NK cells represents a new innovative approach to the optimization and development of novel cancer immunotherapy approaches that enhance NK cell effector functions through modulation of the TNF pathway.