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Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNT\n                    <jats:sup>low<\/jats:sup>\n                    , fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2\n                    <jats:sup>+<\/jats:sup>\n                    cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody\u2013drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell\u00a0state composition between WNT\n                    <jats:sup>hi<\/jats:sup>\n                    LGR5\n                    <jats:sup>+<\/jats:sup>\n                    states\u00a0and WNT\n                    <jats:sup>low<\/jats:sup>\n                    TROP2\n                    <jats:sup>+<\/jats:sup>\n                    fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2\u00a0antibody\u2013drug conjugates selectively target these populations and remodel the tumour cell\u00a0state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10705-2","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:04:22Z","timestamp":1782925462000},"page":"1023-1033","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["TROP2 targeting reveals therapy-driven cell state dynamics in colorectal 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