Postoperative bacterial infection promotes tumor metastasis via neutrophil-mediated NK cell dysfunction

Distant metastasis is the leading cause of cancer-related mortality, and inflammation plays a significant role in promoting cancer metastasis. Patients undergoing surgery are generally more susceptible to bacterial infection due to surgical trauma and immunological dysfunction. However, the extent to which bacterial inflammation contributes to tumor progression remains unclear. We conducted an integrative analysis of colorectal cancer patients who underwent curative surgery and experimental animal models to investigate the impact of anastomotic leakage on oncological outcomes. Using a cecal ligation and puncture (CLP) mouse model, we analyzed NK cell infiltration and activity in peripheral blood and liver tissues under infectious inflammatory conditions, together with NET deposition in metastatic niches. Finally, we examined the efficacy of NET degradation or CTSG inhibition in restoring NK cell-mediated tumor cytotoxicity and preventing tumor metastasis in two distinct mouse models of severe infection. Postoperative infectious complications were associated with increased metastatic recurrence. In mouse models, infection-induced NETs impaired NK cell proliferation and function. Mechanistically, NET-associated CTSG contributed to reduced surface NKp46 expression, a key activating receptor on NK cells. Disruption of NETs or pharmacological inhibition of CTSG restored NK cell cytotoxicity and suppressed metastatic colonization. NET-associated CTSG undermines NK cell-mediated tumor surveillance, contributing to infection-driven metastasis. Targeting the NET-CTSG axis may offer a novel therapeutic strategy to prevent postoperative metastatic progression.