Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

自噬介导的化疗耐药是乳腺癌治疗失败和预后不良的核心机制。乳腺癌化疗耐药性被认为受肿瘤相关巨噬细胞 （TAM） 的影响，其中 C-X-C 基序趋化因子配体 1 （CXCL1） 是分泌最丰富的细胞因子。然而，它在介导自噬相关化疗耐药中的作用仍然未知。本研究旨在探讨 TAMs/CXCL1 诱导乳腺癌自噬介导的化疗耐药的分子机制。研究发现，TAMs/CXCL1 通过体外自噬激活促进乳腺癌细胞的化疗耐药，CXCL1 沉默可通过自噬抑制增强紫杉醇耐药乳腺癌细胞的化疗敏感性。高通量定量 PCR 芯片和随后的靶标验证表明，CXCL1 通过抑制 VHL 介导的 IGF1R 泛素化诱导自噬介导的化疗耐药。然后，升高的 IGF1R 促进 STAT3/HMGB1 信号传导以促进自噬。此外，TAMs/CXCL1 沉默通过抑制乳腺癌小鼠异种移植物的自噬来提高紫杉醇化疗敏感性，临床研究进一步将 CXCL1 与 IGF1R/HMGB1 信号传导以及更短的复发自由生存期联系起来。综上所述，这些结果不仅揭示了 TAMs/CXCL1 信号转导通过增强自噬介导乳腺癌化疗耐药的关键作用，而且还为 IGF1R/STAT3/HMGB1 通路调节自噬的分子机制及其对癌症预后的影响提供了新的思路。