Increased DNA replication and metastasis are hallmarks of cancer progression, while deregulated proliferation often triggers sustained replication stresses in cancer cells. How cancer cells overcome the growth stress and proceed to metastasis remains largely elusive. Proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA replication machinery. Here, we show that phosphorylation of PCNA on tyrosine 211 (pY211-PCNA) regulates DNA metabolism and tumor microenvironment. Abrogation of pY211-PCNA blocks fork processivity, resulting in biogenesis of single-stranded DNA (ssDNA) through a MRE11-dependent mechanism. The cytosolic ssDNA subsequently induces inflammatory cytokines through a cyclic GMP-AMP synthetase (cGAS)-dependent cascade, triggering an anti-tumor immunity by natural killer (NK) cells to suppress distant metastasis. Expression of pY211-PCNA is inversely correlated with cytosolic ssDNA and associated with poor survival in patients with cancer. Our results pave the way to biomarkers and therapies exploiting immune responsiveness to target metastatic cancer. Display omitted •pY211-PCNA is important in maintaining the integrity of replication forks•Inhibition of pY211 leads to biogenesis of cytosolic ssDNA•The cytosolic ssDNA activates the cGAS-STING-cytokine inflammatory pathway•Abrogation of pY211-PCNA induces an anti-tumor immunity mediated by NK cells Wang et al. show that abrogation of Y211 phosphorylation of PCNA leads to replication fork collapse and cytosolic ssDNA, which triggers the cGAS-STING cascade to release type I interferons from tumor cells. Loss of Y211 phosphorylation results in anti-tumor immunity by NK cells and subsequently the suppression of distant metastasis.