Mechanistic insights into fibroblasts in neoadjuvant therapy for esophageal squamous cell carcinoma

Background: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with a poor prognosis, particularly in East Asia, where it accounts for a significant proportion of global cases. Neoadjuvant therapies, including chemoradiotherapy and immunotherapy, have improved resectability and survival outcomes, yet resistance mediated by the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), remains a major challenge. This systematic review aims to elucidate the role of fibroblasts in neoadjuvant therapy resistance in ESCC. Methods: A comprehensive review of the literature was conducted, focusing on studies exploring the molecular and cellular interactions between fibroblasts and ESCC cells in the context of neoadjuvant therapy. Data from clinical trials, preclinical studies, and mechanistic investigations were synthesized to evaluate the contributions of CAFs to therapy resistance, tumor progression, and immune modulation. Results: CAFs within the ESCC TME promote tumor growth, invasion, and metastasis by secreting growth factors, cytokines, and extracellular matrix components. They facilitate resistance to neoadjuvant therapies by upregulating anti-apoptotic pathways, remodeling the TME to impede drug penetration, and suppressing anti-tumor immune responses. Clinical trials, such as KEYNOTE-181 and CheckMate-648, demonstrate improved survival with neoadjuvant chemoimmunotherapy, yet resistance persists in a significant proportion of patients, partly attributable to CAF-mediated mechanisms. Limitations in current research include reliance on simplified preclinical models, methodological inconsistencies, and a lack of integrative studies capturing TME complexity. Conclusion: Fibroblasts, particularly CAFs, play a pivotal role in mediating neoadjuvant therapy resistance in ESCC through intricate interactions within the TME.