What is it about?

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond and exhibit resistance. The “self-eating” machinery possessed by cancer cells, called autophagy, has been attributed to this resistance. Employing several preclinical cancer models, we found that inhibiting an autophagy regulator, PIKfyve, in cancer cells restored a protein complex called the major histocompatibility complex class I (MHC-I) that is essential for the action of immunotherapies. Consequently, inhibition of PIKfyve delayed tumor growth with increased immune effector cells in tumors and significantly improved efficacy of various immunotherapies, including immune checkpoint blockade, adoptive cell therapy, and therapeutic vaccine.

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Why is it important?

Our findings merit further clinical development of PIKfyve inhibition in combination with various immunotherapies to improve patient survival.


Immunotherapy has undeniably transformed the landscape of cancer treatment, offering unprecedented responses and even durable remissions in some cases. However, its efficacy is far from universal, leaving a substantial proportion of patients without tangible benefits. This article delves into the depths of this clinical conundrum, offering a tantalizing solution: targeting PIKfyve to enhance cancer immunotherapy outcomes. At the heart of this research lies the lipid kinase PIKfyve, a multifaceted player in cellular processes such as autophagic flux and lysosomal biogenesis. By inhibiting PIKfyve either genetically or pharmacologically, our study demonstrates a remarkable outcome—upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells. This seemingly subtle alteration holds profound implications, as it leads to enhanced cancer cell killing by CD8+ T cells, the immune warriors tasked with seeking out and destroying malignant cells.

Arul Chinnaiyan
University of Michigan

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This page is a summary of: Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy, Proceedings of the National Academy of Sciences, November 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2314416120.
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