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Sex influences on tumor innervation.

Sarah M Barclay1,2, Jeffrey Barr1, Oduduabasi Isaiah1

  • 1Sanford Research Institute, 2301 East 60th Street north, Sioux Falls, SD, USA.

Biology of Sex Differences
|April 10, 2026
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Summary

Sex influences tumor innervation, with females exhibiting greater nerve infiltration and metastasis following treatment. Standard cancer therapies activate neural pathways, impacting brain function, but this activation is reduced by treatment, correlating with improved behavior.

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Area of Science:

  • Oncology
  • Neuroscience
  • Immunology

Background:

  • Peripheral solid tumors, including oral cancers and melanoma, are infiltrated by nerves.
  • The role of sex in tumor innervation and its impact on the tumor-brain circuit is not well understood.

Purpose of the Study:

  • To investigate the influence of sex on tumor innervation in oral cancers and melanoma.
  • To assess the impact of sex on the tumor-brain neural circuit and associated behavioral changes.
  • To evaluate the effects of standard cancer therapy on tumor innervation, metastasis, and the tumor-brain circuit.

Main Methods:

  • Utilized syngeneic cell lines in mice to model oral cancer and melanoma.
  • Quantified tumor growth, innervation density, and metastasis.
  • Assessed behavioral changes and neural activation in the central nervous system (CNS) projection areas.
  • Administered cisplatin and radiation therapy to evaluate treatment effects.

Main Results:

  • Tumors grew slower and were more innervated in females compared to males.
  • Treatment with cisplatin and radiation increased tumor innervation, particularly in females, and led to increased lung metastasis in treated females.
  • While the tumor-brain circuit itself did not differ by sex, peripheral malignancies activated neurons and glia in CNS projection areas, an effect attenuated by treatment, correlating with improved behavior.

Conclusions:

  • Sex significantly influences peripheral tumor innervation and the activation of CNS projection areas via the tumor-brain circuit.
  • Standard cancer therapies can modulate tumor innervation and neural activation, leading to improved behavior.
  • Targeting the tumor-brain circuit may offer novel therapeutic strategies for cancer patients.