Targeting B7-H3 in Cancer-Associated Fibroblasts Using Nanosystems Suppresses Anaplastic Thyroid Carcinoma Progression.

Abstract

Background: Anaplastic thyroid carcinoma (ATC) represents a rare yet highly malignant histotype of thyroid cancer. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor cell invasion, migration, and angiogenesis and present a potential target for cancer treatment. We aimed to investigate the effects of modulating specific subsets of CAFs on the proliferation, invasion, and migration of ATC. Methods: We developed nanosystems, platelet-derived growth factor receptor (PDGFR-β) targeted-polypeptide-modified poly (β-amino ester) (pBAE) (T-pBAE)/siB7-H3 nanoparticles (NPs), targeting PDGFR-β+ CAFs and featuring B7-H3 knockdown. We evaluated both the targeting efficacy and gene silencing performance of T-pBAE/siB7-H3 NPs, as well as the functional contribution of B7-H3 to CAFs-driven ATC progression. Results: T-pBAE/siB7-H3 NPs were efficiently internalized by CAFs, achieving targeted knockdown of B7-H3 expression. Silencing B7-H3 significantly suppressed the expression of cell division cycle 27 and other cell cycle-related genes, thereby inhibiting CAFs' proliferation. Consequently, CAFs-secreted cytokines (e.g., CCL1 and CCL4) were altered. Through modulation of cytokine receptor activation on ATC cells, this process reduced ATC cell proliferation, invasion, and migration. In mice ATC subcutaneous tumor models, local injection of T-pBAE/siB7-H3 NPs reduced tumor volume. Moreover, the expression of invasive proliferation-related markers (PDGFR-β, Ki-67, CD31), immune evasion-related marker CD163, and chemoresistance-related marker ATP-binding cassette subfamily G member 2 was remarkably downregulated in tumor tissues. Conclusion: This study demonstrates that PDGFR-β polypeptide-modified pBAE could successfully deliver B7-H3 siRNA to CAFs. After knockdown of B7-H3 within CAFs, ATC proliferation, invasion, and migration were inhibited. Overall, our findings revealed that B7-H3 can be a promising therapeutic target for ATC.