Recurrence and
metastasis after resection are still the main challenges in clinical treatment of
breast cancer.
Residual tumor and
cancer stem-like cells are the primary culprits of recurrence and
metastasis. Recent research studies indicate that autophagy is a cytoprotective mechanism of
tumors, which maintains the stemness of
cancer cells and promotes
tumor proliferation and
metastasis. Here, we constructed a "Trojan horse" using neutrophils as the carrier (PH-RL@NEs) to prevent the recurrence and
metastasis of postoperative
breast cancer. Neutrophils, as a "Trojan horse," can quickly respond to postoperative
inflammation and accurately deliver drugs to the
residual tumor site. The
inflammation-triggered "Trojan horse" was then opened to release the
liposomes containing the chemotherapeutic drug
paclitaxel (PTX) and the autophagy inhibitor
hydroxychloroquine (HCQ). We found that HCQ could effectively inhibit
tumor cell autophagy, interfere with
tumor epithelial-mesenchymal transition, and reduce the tumor stem cell-like population. In the orthotopic 4T1 postoperative recurrence models, PTX and HCQ synergistically killed
tumors and regulated the stemness of
tumor cells, thereby significantly inhibiting
tumor recurrence and
metastasis. Our work proved that the inhibition of autophagy to reduce
tumor stemness is feasible and effective, which opens up a new prospect for postoperative
tumor treatment. STATEMENT OF SIGNIFICANCE: The present study aimed to solve the issues of postoperative recurrence and
metastasis of
breast cancer and low efficiency of drug administration after surgery. For this purpose, we constructed neutrophils containing
hydroxychloroquine (HCQ) and
paclitaxel (PTX) co-loaded
liposomes (PH-RL@NEs), which for the first time regulated the stemness of
tumor cells by inhibiting autophagy, thereby inhibiting postoperative recurrence and
metastasis of
breast cancer cells. The results showed that PH-RL@NEs enhanced the targeted drug delivery efficiency, with the help of postoperative
inflammation chemotaxis of neutrophils. HCQ effectively inhibited autophagy of
tumor cells and reduced tumor stem cell-like cells, thus improving the
therapeutic effect in the 4T1 in situ postoperative recurrence model.