Biological and Prognostic Insights into the Prostaglandin D2 Signaling Axis in Lung Adenocarcinoma

Qiang Liu¹Huiguo Chen²Dongfang Tang³Huibiao Zhang³Shaogeng Chen⁴Yiran Meng⁵Boying Zheng⁵Fei Liu⁵Jing Zhou^6*Wen Zhang^7*

• ¹Department of Thoracic Surgery, International Hospital, Peking University, Beijing, Beijing Municipality, China
• ²Department of Cardiothoracic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
• ³Department of Thoracic Surgery, Huadong Hospital, Fudan University, Shanghai, Shanghai Municipality, China
• ⁴Department of Thoracic Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian Province, China
• ⁵Hangzhou Repugene Technology Co., Ltd., Hangzhou, Zhejiang Province, China
• ⁶Department of Thoracic Surgery, Fuyang People's Hospital, Fuyang, Anhui, China, Fuyang, Jiangsu Province, China
• ⁷Department of Thoracic Surgery, Fourth Medical Center of PLA General Hospital, Beiing, China

Tumor metabolism has become central to cancer prognosis and therapy evaluation, but metabolite-mediated intercellular communication remains poorly understood. Here, we employed single-cell RNA sequencing (scRNA-seq) data to investigate the metabolite abundance and intercellular crosstalk events in lung adenocarcinoma (LUAD). Prostaglandin D2 (PGD2) emerged as a key player in the tumor microenvironment, primarily produced by fibroblasts and plasmacytoid dendritic cells (pDCs) via the PTGDS gene and by mast cells via the HPGDS gene. PGD2 signaling was shown to primarily be received by the PGD2 receptor (PTGDR) on NK/T cells and transported by the SLCO2A1 transporter on endothelial cells. CX3CR1+ NK/T cells, which are prominent cytotoxic populations are involved in PGD2 autocrine signaling, while KLRC2+ NK, DNAJB1+ NK cells and CD8+ MAIT cells participate in PGD2 paracrine signaling. PGD2 may also assist lactate efflux via SLCO2A1 on endothelial cells. The clinical relevance of the PGD2 signaling axis was validated across multiple bulk RNA datasets, showing that it is associated with the infiltration of above immune cells such as DNAJB1+ NK cells, and linked to better prognosis in LUAD. Additionally, we found that a risk model developed based on this signaling axis could predict responses of immune therapy in hot and cold tumors, suggesting potential drugs that may benefit low-risk patients. These findings were further supported by RT-qPCR and immunofluorescence data, which confirmed the downregulation of PTGDS and PTGDR in LUAD tumor tissues compared to normal tissues. Collectively, these results suggest that PGD2 and its signaling axis play a significant role in tumor-suppressive and anti-inflammatory effects in LUAD, with potential applications in prognosis management and therapy decision-making.