Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.
© 2025. The Author(s).

The tumour microenvironment (TME) is a highly structured ecosystem that surrounds a tumour and plays a crucial role in tumorigenesis. As one of the most abundant cell types in the TME, tumour-associated-macrophages (TAMs) can promote disease progression and resistance to therapy. Syndecan-3 (SDC3) is a cell-surface heparan sulphate proteoglycan expressed by TAMs, although its functional relevance in these cells remains unknown. Here, we demonstrated that pro-inflammatory cytokines drive the expression of SDC3 on the cell surface of macrophages. Genetic ablation of SDC3 in macrophages led to aberrant proliferation, adhesion and expression of CD40 and CD86 surface markers. Moreover, SDC3 defective macrophages exhibited distinctive gene expression patterns, leading to impaired tumour cell phagocytosis and increased tumour cell proliferation. Mechanistically, a decrease in the secretion of pro-inflammatory cytokines was observed in SDC3 KO macrophages, concomitant with impaired T cell effector functions. Additionally, a higher angiogenic capacity was observed in endothelial cells when co-cultured with macrophages deficient for SDC3, possibly mediated through an increased release of VEGFA, PECAM-1 and IL-8 by SDC3 KO cells. Collectively, we have identified SDC3 as a modulator of macrophage functions aiming at supporting a pro-inflammatory and anti-tumour phenotype in these cells.
© 2025. The Author(s).