Rewiring Tumor Immunity: Targeting PGE2 Signaling in Cancer

Cancer does not simply grow, it actively disables the immune system. Our research seeks to understand and reverse this process, uncovering how tumors evade immune attack and how we can restore effective anti-tumor immunity.

Why do some cancers resist even the most advanced immunotherapies? Our lab addresses this fundamental question by focusing on prostaglandin E2 (PGE2), an inflammatory lipid mediator that tumors exploit to evade immune attack. Among its receptors, EP2 and EP4 have emerged as promising therapeutic targets, and several inhibitors are already undergoing clinical trials. However, the mechanisms by which these drugs act and the contexts in which they are effective remain largely unclear.

To tackle this problem, we combine in vivo cancer models with cutting-edge single-cell technologies. Using immune-resistant tumor models, we found that PGE2 signaling drives the formation of a highly suppressive tumor microenvironment by promoting regulatory T cells and activating tumor-supportive myeloid cells, thereby dampening anti-tumor immunity (Thumkeo et al., Cell Reports, 2022). These findings suggest that PGE2 plays a central role in shaping tumors that are refractory to current immunotherapies.

We have extended these observations to human cancers through single-cell analysis of clinical samples. Our data reveal that EP4, and to a lesser extent EP2, is broadly expressed across tumor-infiltrating immune cells, but in a dynamic and context-dependent manner. This led us to investigate how PGE2 signaling affects immune cell function at the molecular level. Our mechanistic studies uncovered that PGE2 does not simply suppress immune cells but actively reprograms them. In CD8 T cells, prolonged exposure to PGE2 inhibits IL-2 signaling and disrupts both mitochondrial function and glycolysis, resulting in impaired proliferation, migration, and tumor-killing activity. Based on these findings, we propose that tumors establish a previously unrecognized “metabolic barrier” that limits effective anti-tumor immunity (Punyawatthananukool et al., Nature Communications, 2024).

Notably, recent independent studies further demonstrate that PGE2 promotes T cell exhaustion (Lacher et al., Nature, 2024; Morotti et al., Nature, 2024), supporting the idea that multiple layers of PGE2-mediated immunosuppression coexist within the tumor microenvironment. Our current goal is to integrate these mechanisms and define their hierarchy in human cancers.

To achieve this, we employ an interdisciplinary approach that integrates single-cell and spatial transcriptomics, functional immunology, and imaging of immune cells  (Thumkeo et al., Science Advances, 2020; Thumkeo & Narumiya, Structure, 2021; Prasongtanakij at al. Eur J Cell Biol, 2025). Through these efforts, we aim to identify the patients who will benefit most from EP2/EP4-targeted therapies and to contribute to the development of next-generation cancer immunotherapies.

For prospective students and researchers, our lab offers the opportunity to work at the interface of immunology, pharmacology, and cancer biology, using state-of-the-art technologies to address clinically relevant questions. Our goal is not only to generate high-impact discoveries, but also to train the next generation of scientists to think critically and tackle complex biological systems.