Purpose <p>To evaluate the predictive value of Slug-positive circulating tumor cells (CTCs) for responses to neoadjuvant chemotherapy in mesenchymal malignancies.</p> Methods <p>Prospective observational analysis of 59 patients receiving neoadjuvant chemotherapy. Peripheral blood was collected pre-treatment for CTC classification. Chemotherapy response was defined as complete response or partial response. Logistic regression identified factors associated with poor response. A combined model integrating Slug⁺ epithelial CTCs (ECTCs) and Slug⁺ mesenchymal CTCs (MCTCs) was developed. Receiver operating characteristic (ROC) analysis assessed predictive performance; Cox regression evaluated long-term outcomes.</p> Results <p>Responders had lower Slug⁺ MCTCs (2.12 ± 1.84 vs. 3.85 ± 2.25) and higher Slug⁺ ECTCs. The combined model showed superior predictive ability (AUC = 0.873) versus single CTC subtypes. Patients with predicted probability &gt; 0.62 were responders. Cox analysis indicated the model predicted long-term prognosis when Slug⁺ MCTCs and Slug⁺ ECTCs were not simultaneously zero.</p> Conclusions <p>Phenotypic heterogeneity influences neoadjuvant chemotherapy response. High Slug⁺ MCTCs and low Slug⁺ ECTCs indicate insensitivity. The combined model showed promising performance for identifying treatment response and potential prognostic relevance in this prospective cohort.</p>