Melanoma Immunotherapy Resistance Reversed by Blocking HPGDS
Source: Inside Precision Medicine, April 2025
A new study led by Max Mazzone, professor at the VIB-KU Leuven Center for Cancer Biology identifies the enzyme hematopoietic prostaglandin D synthase (HPGDS) as a key driver of immunotherapy resistance in melanoma. Published in Cancer Discovery, the findings highlight that targeting HPGDS can reprogram tumor-associated macrophages (TAMs) and sensitize tumors to immune checkpoint blockade therapies, offering a promising new strategy for patients who currently fail to respond.
Approximately 65% of melanoma patients do not benefit from immune checkpoint inhibitors such as anti-PD1 therapies. TAMs—immune cells abundant in tumors—are known to promote tumor growth and suppress T-cell activity. The team discovered that a subset of TAMs expressing high levels of HPGDS produces prostaglandin D2 (PGD2), a lipid mediator that supports an immunosuppressive tumor environment by acting both directly on macrophages and indirectly by hindering CD8+ T cell recruitment and function.
“HPGDS installs a Prostaglandin-D2 (PGD2) autocrine loop in TAMs via DP1 and DP2 activation that sustains their pro-tumoral phenotype and promotes paracrine inhibition of CD8+ T cells,” the authors wrote?.