ARTICLE ABSTRACTPurpose: Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease.Experimental Design: Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre- and post-influenza vaccination using both in vivo and ex vivo assays.Results: Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNα is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients.Conclusion: These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease. Clin Cancer Res; 19(18); 5104–15. ©2013 AACR.