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.
Using genetic models and pharmacological inhibitors, the researchers demonstrated that blocking HPGDS reshapes the tumor microenvironment. Macrophages shifted from a tumor-supporting to a tumor-fighting phenotype, T cells became more active, tumor blood vessels normalized, and cancer spread was reduced. This reprogramming made previously resistant tumors responsive to anti-PD1 therapy.
Importantly, this therapeutic effect extended beyond melanoma. In mouse models of pancreatic ductal adenocarcinoma—a cancer notoriously resistant to immunotherapy—combining HPGDS inhibition with anti-PD1 significantly improved outcomes. Moreover, patient-derived tumor organoids treated with an HPGDS inhibitor showed increased infiltration and activity of TNFα-producing CD8+ T cells.
“Targeting HPGDS not only enhanced the recruitment and activation of T cells per se, but also showed promise in overcoming resistance to existing therapies,” said Mazzone.
These findings suggest that the HPGDS/PGD2/DP1 axis acts as a critical immune suppressor in tumors and presents a new therapeutic opportunity. As HPGDS is expressed by a specific subset of macrophages and not in normal tissue macrophages, targeting it could offer a more selective and potentially safer alternative to other macrophage-directed therapies.
The authors concluded: “We suggest HPGDS inhibition as a promising strategy to treat refractory tumors to current immunotherapies or to overcome acquired resistance to ICB.”
Clinical testing of HPGDS inhibitors, already underway for other diseases, could pave the way for new combination immunotherapies in cancer.
