Self-promoting ferroptosis amplifier based on DKK1 inhibition for metastatic cancer therapy.

Ferroptosis therapy holds great potential in metastatic cancer treatment. Whereas, Dickkopf-related protein-1 (DKK1) that highly expressed in various tumors might contribute to low ferroptosis sensitivity of tumor cells, which imposed restrictions on ferroptosis therapy. Our research revealed that DKK1 inhibition could sensitive tumor cells to ferroptosis by obstructing the cystine-GSH-GPX4 axis and the CoQ10-FSP1 axis. Moreover, DKK1 inhibition facilitated dormancy of tumor cells, thereby inhibiting their metastatic proliferation. Encouraged by that, a strategy combining DKK1 inhibition with ferroptosis induction was innovatively proposed for metastatic cancer treatment. And a sulfated hyaluronic acid (SHA)-functionalized liposome co-encapsulating DKK1 inhibitor (Gallocyanine) and ferroptosis inducer (RSL3) was developed for this purpose. The constructed SLip/G+R simultaneously targeted primary tumors, circulating tumor cells and tumor metastases by not only binding to P-selectin/CD44 on tumor cells, but also hitchhiking on activated platelets with tumor cells tendency. Particularly, SLip/G+R increased P-selectin/CD44 on tumor cells through DKK1 inhibition, providing more targets for itself and enhancing the targeting effect in a "self-promoting" manner. Due to the self-promoting ferroptosis amplification, SLip/G+R exerted excellent anti-tumor and anti-metastasis efficacy. Overall, this study provided a new idea for efficiently eliminating metastatic tumor cells. It is conducive to promoting the development of ferroptosis therapy, and is of great significance for metastatic cancer treatment.