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Peer-reviewedCC BY-NC-NDCancer letters

Endometriosis from Initiation to Innovation: Immune Microenvironments, Clonal Lesion Biology, and the Emerging Therapeutic Pipeline

  • Bindu Santhamma1
  • Jessica Chacon2
  • Eva Deemer3
  • Dorota Stary4
  • Shayla A. Hernandez5
  • Ramadevi Subramani5
  • Rajkumar Lakshmanaswamy5
  • Klaus J. Nickisch6
  • Surinder Batra7
  • Hareesh B. Nair5
7 affiliations
  1. 1Evestra, Inc, San Antonio, TX, USA
  2. 2Department of Medical Education, Texas Tech University Health Science Center El Paso, TX, USA
  3. 3Environmental and Occupational Health Sciences, University of Texas Houston, El Paso, TX, USA
  4. 4Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Cracow, Poland
  5. 5Department of Molecular and Translational Medicine, Texas Tech University Health Science Center El Paso, TX, USA
  6. 6VaRi Biosciences, Berlin, Germany
  7. 7Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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Abstract

Endometriosis is a chronic, estrogen-dependent inflammatory disease that, despite its benign histology, displays several cancer-relevant features, including clonal expansion, somatic alteration-associated lesion evolution, tissue invasion, apoptosis resistance, immune evasion, angiogenesis, fibrosis, and metabolic adaptation. These features are particularly important in ovarian endometriosis, where recurrent hemorrhage, iron-driven oxidative stress, and chronic inflammatory remodeling may promote malignant transformation. This review examines endometriosis through an oncologic framework by integrating current evidence on disease initiation, clonal lesion evolution, and the peritoneal, ovarian, and deep-infiltrating microenvironments. We discuss how epithelial, stromal, immune, endothelial, mesothelial, and neural components cooperate to support lesion survival, dissemination, vascularization, fibrosis, neuroinflammation, and treatment resistance. Particular attention is given to cancer-associated molecular programs, including PI3K-AKT-mTOR, RAS-MAPK, WNT/β-catenin, hypoxia, oxidative-stress, inflammatory, and epigenetic signaling, and their relationship to endometriosis-associated ovarian cancer. We also critically evaluate animal models, organoids, three-dimensional scaffolds, and microfluidic systems for their ability to reproduce lesion heterogeneity, microenvironmental interactions, therapeutic responses, and malignant progression. Finally, we assess current and emerging therapeutic strategies, emphasizing non-hormonal interventions directed against inflammatory, immune, fibrotic, angiogenic, metabolic, and oncogenic vulnerabilities, together with biomarker-guided and fertility-sparing approaches. Viewing endometriosis as a cancer-relevant inflammatory and clonal disease may reveal actionable mechanisms for precision treatment and interception of endometriosis-associated malignancy.

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Cite

BibTeXRIS
BibTeX
@article{santhamma2026endometriosis,
  title = {{Endometriosis from Initiation to Innovation: Immune Microenvironments, Clonal Lesion Biology, and the Emerging Therapeutic Pipeline}},
  author = {Bindu Santhamma and Jessica Chacon and Eva Deemer and Dorota Stary and Shayla A. Hernandez and Ramadevi Subramani and Rajkumar Lakshmanaswamy and Klaus J. Nickisch and Surinder Batra and Hareesh B. Nair},
  journal = {Cancer letters},
  year = {2026},
  month = sep,
  doi = {10.1016/j.canlet.2026.218845},
  url = {https://doi.org/10.1016/j.canlet.2026.218845},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Endometriosis from Initiation to Innovation: Immune Microenvironments, Clonal Lesion Biology, and the Emerging Therapeutic Pipeline
AU  - Bindu Santhamma
AU  - Jessica Chacon
AU  - Eva Deemer
AU  - Dorota Stary
AU  - Shayla A. Hernandez
AU  - Ramadevi Subramani
AU  - Rajkumar Lakshmanaswamy
AU  - Klaus J. Nickisch
AU  - Surinder Batra
AU  - Hareesh B. Nair
PY  - 2026
DA  - 2026/09/19
JO  - Cancer letters
DO  - 10.1016/j.canlet.2026.218845
UR  - https://doi.org/10.1016/j.canlet.2026.218845
AB  - Endometriosis is a chronic, estrogen-dependent inflammatory disease that, despite its benign histology, displays several cancer-relevant features, including clonal expansion, somatic alteration-associated lesion evolution, tissue invasion, apoptosis resistance, immune evasion, angiogenesis, fibrosis, and metabolic adaptation. These features are particularly important in ovarian endometriosis, where recurrent hemorrhage, iron-driven oxidative stress, and chronic inflammatory remodeling may promote malignant transformation. This review examines endometriosis through an oncologic framework by integrating current evidence on disease initiation, clonal lesion evolution, and the peritoneal, ovarian, and deep-infiltrating microenvironments. We discuss how epithelial, stromal, immune, endothelial, mesothelial, and neural components cooperate to support lesion survival, dissemination, vascularization, fibrosis, neuroinflammation, and treatment resistance. Particular attention is given to cancer-associated molecular programs, including PI3K-AKT-mTOR, RAS-MAPK, WNT/β-catenin, hypoxia, oxidative-stress, inflammatory, and epigenetic signaling, and their relationship to endometriosis-associated ovarian cancer. We also critically evaluate animal models, organoids, three-dimensional scaffolds, and microfluidic systems for their ability to reproduce lesion heterogeneity, microenvironmental interactions, therapeutic responses, and malignant progression. Finally, we assess current and emerging therapeutic strategies, emphasizing non-hormonal interventions directed against inflammatory, immune, fibrotic, angiogenic, metabolic, and oncogenic vulnerabilities, together with biomarker-guided and fertility-sparing approaches. Viewing endometriosis as a cancer-relevant inflammatory and clonal disease may reveal actionable mechanisms for precision treatment and interception of endometriosis-associated malignancy.
SN  - 0304-3835
SN  - 1872-7980
ER  -