DATE2025.09.01 #Press Releases

Why Does Cancer Immunotherapy Stop Working?

―Uncovering the Identity of Treatment-Resistant “Malignant Subclones”―

Summary

A research group led by Dr. Kota Umeda (Collaborating Researcher), Dr. Nobuyuki Tanaka (Senior Lecturer), and Prof. Mototsugu Oya (Professor) of the Department of Urology, Keio University School of Medicine, together with Prof. Tatsuhiko Tsunoda (School of Science, The University of Tokyo; also Professor at the Graduate School of Frontier Sciences, The University of Tokyo) and Dr. Takashi Kamatani (Lecturer, Division of AI Technology Development, AI and Big Data Research Unit, M&D Data Science Center, Tokyo University of Science), has elucidated how metastatic urothelial carcinoma acquires resistance to immune checkpoint inhibitors.

The team demonstrated that, during the survival process of cancer cells, repeated oncogenic mutations generate a variety of malignant subclones. These subclones establish an immunosuppressive microenvironment that immune checkpoint inhibitors cannot overcome.

In this study, the researchers focused on differences in the response to anti-PD-1 therapy across metastatic tumor sites in autopsy cases of urothelial carcinoma. Multi-regional tumor omics analyses revealed that certain malignant subclones acquired specific genetic alterations during treatment, driving disease progression. Furthermore, spatial transcriptomics and single-cell analyses showed that these malignant subclones adapt to their local niches and establish their own unique immunosuppressive environments.

Recently, attention has been drawn to the so-called “bad apple” concept: the coexistence of malignant subclones within tumors is linked to poor prognosis, as even a few highly aggressive subclones can dictate the overall behavior of the tumor. The findings of this study provide important insights for developing future cancer immunotherapies, including subclone-targeted strategies and modifications of the immune microenvironment, aimed at enhancing the efficacy of immune checkpoint inhibitors.

The results were published online in Nature Communications on August 27, 2025 (UK Summer Time).

Figure:Malignant subclones #12 and #14 coexist within the same patient while exhibiting distinct cancer profiles at the single-cell level, each establishing its own immunosuppressive microenvironment.

Links

Keio University, Science Tokyo

Journals

Journal name	Nature Communications
Title of paper	Clonal diversity shapes the tumour microenvironment leading to distinct immunotherapy responses in metastatic urothelial carcinoma