Abstract
SUMMARY
NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor–immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.
eTOC blurb
Nishimura et al. show that NECTIN4, the target of enfortumab vedotin, defines subtype-dependent tumor–immune states in bladder cancer. In basal/squamous tumors, NECTIN4 restrains inflammatory-mesenchymal programs and marks a CD8-rich microenvironment linked to checkpoint inhibitor response, whereas NECTIN4-low models show preferential sensitivity to HDAC inhibition.
HIGHLIGHTS
NECTIN4 is a subtype-dependent regulator of tumor state, not just an ADC target
NECTIN4-high Ba/Sq tumors exhibit a coordinated CD8-inflamed microenvironment
Nectin4 drives CD8 T cell-dependent tumor control in immunocompetent mice
NECTIN4 couples EV targetability to a checkpoint-responsive immune context