Findings revealed a novel crosstalk between tumor-associated neutrophils (TANs) and colorectal cancer (CRC) cells implicating the secreted AGR2(anterior gradient-2)–CD98hc(heavy chain of CD98)–xCT axis that encourages metastasis and influences the outcomes of patients suffering from CRC.

• This study included CRC patients, neutrophil-specific Agr2 knockout (Agr2 ^f/f ;Mrp-Cre) mice, and in vitro and in vivo analyses, to determine the cellular source for secreted AGR2 in the tumor microenvironment (TME) and underlying mechanisms mediating secreted AGR2’s effects.

• TANs were identified as a main cell type for secreting AGR2 in the TME of CRC, and migration of CRC cells was promoted by TANs-secreted AGR2.

• In mice, CRC liver metastases were relieved by neutrophils-specific ablation of Agr2.

• CD98hc was the functional receptor for secreted AGR2.

• Mechanistically, increase in xCT activity was brought about by secreted AGR2 in a CD98hc-dependent manner, subsequently activating Ras homologue family member A/Rho-related protein kinase 2 cascade.

• Via the C-X-C motif chemokine 2, active recruitment of TANs by CRC cells occurred.

• CRC-derived transforming growth factor beta 1 (TGF-β1) educated peripheral blood neutrophils to become AGR2 ⁺ TANs that secrete AGR2.

• Factors correlated with poor prognosis of CRC patients were: abundant infiltration of AGR2 ⁺ TANs and high expression of TGF-β1 and CD98hc–xCT.