Tumor microenvironment: an evil nexus promoting aggressive head and neck squamous cell carcinoma and avenue for targeted therapy

Ajaz A. Bhat, Parvaiz Yousuf, Nissar A. Wani, Arshi Rizwan, Shyam S. Chauhan, Mushtaq A. Siddiqi, Davide Bedognetti, Wael El-Rifai, Michael P. Frenneaux, Surinder K. Batra, Mohammad Haris, Muzafar A. Macha

Research output: Contribution to journalReview articlepeer-review

42 Scopus citations


Head and neck squamous cell carcinoma (HNSCC) is a very aggressive disease with a poor prognosis for advanced-stage tumors. Recent clinical, genomic, and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC. Despite significant advances in multimodal therapeutic interventions, failure to cure and recurrence are common and account for most deaths. It is becoming increasingly apparent that tumor microenvironment (TME) plays a critical role in HNSCC tumorigenesis, promotes the evolution of aggressive tumors and resistance to therapy, and thereby adversely affects the prognosis. A complete understanding of the TME factors, together with the highly complex tumor–stromal interactions, can lead to new therapeutic interventions in HNSCC. Interestingly, different molecular and immune landscapes between HPV+ve and HPV−ve (human papillomavirus) HNSCC tumors offer new opportunities for developing individualized, targeted chemoimmunotherapy (CIT) regimen. This review highlights the current understanding of the complexity between HPV+ve and HPV−ve HNSCC TME and various tumor–stromal cross-talk modulating processes, including epithelial–mesenchymal transition (EMT), anoikis resistance, angiogenesis, immune surveillance, metastatic niche, therapeutic resistance, and development of an aggressive tumor phenotype. Furthermore, we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV+ve and HPV−ve HNSCC.

Original languageEnglish (US)
Article number12
JournalSignal Transduction and Targeted Therapy
Issue number1
StatePublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Cancer Research


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