NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer
- 1Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Abstract
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.
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BibTeX
@misc{nishimura2026nectin4,
title = {{NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer}},
author = {K. Nishimura and R. Maenosono and T. Owari and M. Sakamoto and T. Nishino and K. Hirosuna and T. Tsujino and T. Izumi-Tamura and Y. Yoshikawa and M. Azuma and S. Inoue and A. Kawachi and A. Ishida and K. Nishimori and J. Mukohyama and N. Shinohara and M. Sakumoto and M. Amisaki and K. Okuyama and M. Ishida and M. Ajiro and Y. Hirose and Y. Suzuki and H. Nishikawa and H. Azuma and F. L. F. Carvalho and A. S. Kibel and L. Jia and S. Koyama and T. Yoshino and K. Komura and A. Yoshimi},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757381},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer
AU - K. Nishimura
AU - R. Maenosono
AU - T. Owari
AU - M. Sakamoto
AU - T. Nishino
AU - K. Hirosuna
AU - T. Tsujino
AU - T. Izumi-Tamura
AU - Y. Yoshikawa
AU - M. Azuma
AU - S. Inoue
AU - A. Kawachi
AU - A. Ishida
AU - K. Nishimori
AU - J. Mukohyama
AU - N. Shinohara
AU - M. Sakumoto
AU - M. Amisaki
AU - K. Okuyama
AU - M. Ishida
AU - M. Ajiro
AU - Y. Hirose
AU - Y. Suzuki
AU - H. Nishikawa
AU - H. Azuma
AU - F. L. F. Carvalho
AU - A. S. Kibel
AU - L. Jia
AU - S. Koyama
AU - T. Yoshino
AU - K. Komura
AU - A. Yoshimi
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757381
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757381v1
AB - 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.
ER -