IGF2BP2 remodels the lung metastatic immune microenvironment to promote bladder cancer metastasis.

Bladder cancer lung metastasis poses a major therapeutic challenge because of pronounced tumor heterogeneity. However, the mechanisms regulating bladder cancer metastasis remain elusive. Here, we established a lung-tropic bladder cancer subline through iterative in vivo selection, enabling stepwise enrichment of metastatic competence while minimizing intratumoral variability. Using integrated multiomics analyses combined with functional validation, we identified an IGF2BP2-m⁶A-complement axis that is progressively engaged during metastatic evolution and contributes to lung colonization by bladder cancer cells. IGF2BP2 expression increased stepwise during the metastatic cascade and selectively enhanced the translation of m⁶A-modified complement C3 mRNA through direct binding to its 3' region, without altering transcript abundance. Tumor-derived C3 is subsequently processed, thereby promoting neutrophil recruitment and phenotypic remodeling toward a prometastatic, T3-like state. Single-cell transcriptomic profiling revealed that loss of IGF2BP2 disrupted neutrophil recruitment and was accompanied by enhanced T-cell proliferative activity within lung metastatic lesions. Genetic ablation or pharmacological inhibition of IGF2BP2 attenuated neutrophil accumulation and significantly restricted metastatic outgrowth in vivo. Consistent with these experimental findings, elevated IGF2BP2 expression in clinical bladder cancer specimens correlated with advanced disease stage, increased metastatic risk, and poor patient survival. Collectively, our findings reveal a translationally regulated complement-immune circuit that shapes the lung metastatic microenvironment and identify IGF2BP2 as a potential therapeutic target in metastatic bladder cancer.