Open Access

REVIEW

Dysregulated PI3K/AKT signaling in oral squamous cell carcinoma: The tumor microenvironment and epigenetic modifiers as key drivers

VINOTHKUMAR VEERASAMY¹, VEERAVARMAL VEERAN², SIDDAVARAM NAGINI^1,3,*

1 Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, 608002, Tamil Nadu, India
2 Division of Oral and Maxillofacial Pathology, Government Dental College and Hospital, Dr. MGR Medical University, Cuddalore District, Annamalainagar, 608002, Tamil Nadu, India
3 Scientific Section, World Neem Organization, Mumbai, 400101, Maharashtra, India

* Corresponding Author: SIDDAVARAM NAGINI. Email:

Oncology Research 2025, 33(8), 1835-1860. https://doi.org/10.32604/or.2025.064010

Received 01 February 2025; Accepted 20 May 2025; Issue published 18 July 2025

Abstract

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway is one of the most frequently dysregulated signaling networks in oral squamous cell carcinoma (OSCC). Although the tumor microenvironment (TME) and epigenetic modifiers are recognized to play a pivotal role in aberrant activation of the PI3K/AKT pathway in OSCC, the available evidence is fragmentary and a comprehensive analysis is warranted. This review evaluates the intricate mechanisms by which various components of the TME facilitate proliferation, apoptosis evasion, invasion, migration, angiogenesis, metastasis, as well as therapy resistance in OSCC through activation of PI3K/AKT signalling. The review has also analysed how epigenetic modifiers such as DNA methylation, histone modifications, and noncoding RNAs that have emerged as key players in orchestrating OSCC development and progression influence the PI3K/AKT pathway. Preclinical studies and clinical trials on the efficacy of PI3K/AKT inhibitors as viable options for OSCC treatment are discussed. Overall, this review supports the tenet that the PI3K/AKT pathway, which functions as a central hub through crosstalk with several oncogenic signaling pathways and overarching impact on all the hallmark traits of cancer, offers immense potential as a biomarker and oncotherapeutic target for OSCC.

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