QPCTL, short for glutaminyl-peptide cyclotransferase-like protein, is an intracellular enzyme. It primarily catalyzes the cyclization of N-terminal glutamine or glutamate to pyroglutamate (pGlu) [1]. This function modifies proteins like CD47, regulating its interaction with SIRPα, and also cyclizes N-termini of chemokines such as CCL2, CCL7, and CX3CL1, influencing the tumor microenvironment, inflammatory responses, and phagocytosis of tumor cells by immune cells [1]. It is thus considered a valuable therapeutic target for several human diseases [1].

In mouse models, knockout of Qpctl disrupted monocyte homeostasis, attenuated tumor growth, and reshaped myeloid cell infiltration. Monocyte-derived populations with immunosuppressive and pro-angiogenic profiles were lost [2]. Qpctl deficiency in a syngeneic mouse melanoma model altered the intra-tumoral monocyte-to-macrophage ratio, increased pro-inflammatory cancer-associated fibroblasts, and led to an increased IFN and decreased TGF-β transcriptional response signature in tumor cells. Qpctl deletion also synergized with anti-PD-L1 therapy, sensitizing a melanoma model to anti-checkpoint therapy [3]. In glioma, higher QPCTL expression was associated with high-grade malignancy, advanced tumor stage, and shorter overall survival. Glioma with QPCTL deficiency had fewer infiltrated immune cells [4].

In conclusion, QPCTL plays essential roles in regulating chemokine function, myeloid cell infiltration, and the tumor microenvironment. Studies using Qpctl knockout mouse models have revealed its significance in cancer-related processes, especially in tumor immunity and glioma progression, suggesting that targeting QPCTL could be a promising strategy for cancer immunotherapy [2,3,4].

References:

1. Yu, Lei, Sun, Yaoliang, Xie, Longyan, Wang, Ping, Xu, Shilin. 2025. Targeting QPCTL: An Emerging Therapeutic Opportunity. In Journal of medicinal chemistry, 68, 929-943. doi:10.1021/acs.jmedchem.4c02247. https://pubmed.ncbi.nlm.nih.gov/39746038/

2. Barreira da Silva, Rosa, Leitao, Ricardo M, Pechuan-Jorge, Ximo, Mellman, Ira, Albert, Matthew L. 2022. Loss of the intracellular enzyme QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. In Nature immunology, 23, 568-580. doi:10.1038/s41590-022-01153-x. https://pubmed.ncbi.nlm.nih.gov/35314846/

3. Bresser, Kaspar, Logtenberg, Meike E W, Toebes, Mireille, Kroese, Lona J, Schumacher, Ton N. 2022. QPCTL regulates macrophage and monocyte abundance and inflammatory signatures in the tumor microenvironment. In Oncoimmunology, 11, 2049486. doi:10.1080/2162402X.2022.2049486. https://pubmed.ncbi.nlm.nih.gov/35309731/

4. Liu, Yu'e, Lu, Shaojuan, Sun, Yihong, Shi, Yufeng, Zhao, Kaijun. 2023. Deciphering the role of QPCTL in glioma progression and cancer immunotherapy. In Frontiers in immunology, 14, 1166377. doi:10.3389/fimmu.2023.1166377. https://pubmed.ncbi.nlm.nih.gov/37063864/