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Updated: Aug 30, 2025

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Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive

Yan Tang1, David J Kwiatkowski2, Elizabeth P Henske3

  • 1Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Nature Communications
|August 26, 2022
PubMed

Insights

Stem-like tumor cells (SLS) with hyperactive mTORC1 drive T cell dysfunction and resist rapamycin. Midkine (MDK) inhibition synergizes with rapamycin, offering a potential therapeutic strategy for Tuberous Sclerosis Complex (TSC) tumors.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling is implicated in various cancers, including Tuberous Sclerosis Complex (TSC).
  • Rapalogs are standard treatments for TSC tumors, but their clinical efficacy is often limited by resistance.

Purpose of the Study:

  • To investigate the mechanisms underlying rapamycin resistance in TSC tumors.
  • To identify novel therapeutic targets for TSC-associated malignancies.

Main Methods:

  • Integrative analysis of single-cell transcriptomics, T cell receptor (TCR) sequencing, and spatial transcriptomics.
  • In vitro and in vivo studies involving TSC cell lines and rapamycin/MDK inhibition.

Main Results:

  • A stem-like tumor cell state (SLS) was identified, characterized by mTORC1 hyperactivity and resistance to rapamycin.
  • SLS cells promote T cell dysfunction through immunosuppressive macrophages and high expression of midkine (MDK).
  • Inhibition of MDK synergizes with rapamycin to reduce tumor growth.

Conclusions:

  • Stem-like tumor cells employ autocrine resistance and paracrine immune suppression mechanisms for survival.
  • Targeting MDK in combination with rapamycin presents a promising therapeutic approach for TSC tumors.

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