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Reimagining HER2 therapy: Bridging oncogene addiction and immune modulation

Luke Tillman1, Lajos Pusztai2, Seth A Wander3

  • 1School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, UK.

Cancer Cell
|May 21, 2026
PubMed

Insights

Human epidermal growth factor receptor 2 (HER2) drives cancer by altering the tumor microenvironment, creating immune resistance. Strategies targeting HER2 must address its immunomodulatory effects for improved cancer treatment efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Human epidermal growth factor receptor 2 (HER2) is a key oncogenic driver in various cancers.
  • HER2 signaling extends beyond direct tumor cell proliferation to profoundly influence the tumor microenvironment.
  • This influence includes suppression of antigen presentation and promotion of immune checkpoints, fostering an immune-resistant tumor state.

Purpose of the Study:

  • To elucidate the immunomodulatory roles of HER2 in the tumor microenvironment.
  • To discuss strategies for enhancing HER2-targeted therapies by addressing immune evasion mechanisms.
  • To highlight the importance of overcoming HER2-driven immunosuppression for effective cancer control.

Main Methods:

  • Review of existing literature on HER2 signaling and tumor immunology.
  • Analysis of HER2's impact on immune cell function and cytokine profiles within the tumor microenvironment.
  • Synthesis of data to propose therapeutic strategies.

Main Results:

  • HER2 actively remodels the tumor microenvironment to suppress anti-tumor immunity.
  • Key mechanisms include reduced antigen presentation and increased immune checkpoint expression.
  • Cytokine-mediated suppression is also a significant factor in HER2-driven immune resistance.

Conclusions:

  • HER2-targeted therapies require integration with immunomodulatory strategies for optimal efficacy.
  • Addressing HER2-driven immunosuppression is critical for achieving durable tumor control.
  • Future therapeutic approaches should focus on overcoming the immune-resistant phenotype induced by HER2.

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