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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Lip Squamous Cell Carcinoma: A Conceptual Framework for Integrating Molecular, Immune and Microenvironmental Drivers

  • Ylli Alicka1
  • Skender Topi1
  • Elona Gaxhja1
  • Gianluca Baldini2
  • Gino Orsini2,3
  • Davide Pietropaoli2
  • Maria Grazia Cifone2
  • Maurizio Giuliani2
  • Serena Altamura4
4 affiliations
  1. 1Faculty of Medical Technical Sciences, University of Elbasan “Aleksandër Xhuvani’”, 3001 Elbasan, Albania
  2. 2Department of Life, Health & Environment Sciences, University of L’Aquila, 67100 L’Aquila, Italy
  3. 3Unit of Plastic and Reconstructive Surgery, Casa di Cura “DI LORENZO”, 67051 Avezzano, Italy
  4. 4Department of Physical & Chemical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
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Abstract

Lip squamous cell carcinoma (LSCC) is a distinct subtype of head and neck squamous cell carcinoma strongly associated with ultraviolet (UV) radiation exposure and characterized by unique molecular, immune, and microenvironmental features. Although UV-induced photodamage represents the principal initiating event, increasing evidence indicates that LSCC progression results from complex interactions among genetic and epigenetic alterations, dysregulated signaling pathways, chronic inflammation, immune dysregulation, host–microbiome dynamics, and tumor microenvironment (TME) remodeling. Recent advances have expanded the traditional view of LSCC by highlighting the contributions of UV-induced DNA damage, tumor protein p53 (TP53) alterations, epigenetic reprogramming, aberrant activation of key signaling pathways, and progressive immune escape mechanisms. In parallel, growing attention has focused on the role of cancer-associated fibroblasts (CAFs), stromal remodeling, microbial dysbiosis, and disruption of the microbiome–immune–metabolic axis as important modulators of disease progression and biological heterogeneity. Emerging biomarkers, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), epigenetic signatures, liquid-biopsy analytes, immune-related markers, and microbiome-associated profiles, together with artificial intelligence (AI)-based analytical approaches, are creating new opportunities for diagnosis, risk stratification, disease monitoring, and precision oncology. Rather than providing a conventional descriptive overview, this review proposes an integrated conceptual framework in which molecular, immune, microbial, and microenvironmental drivers interact through continuous bidirectional crosstalk to shape LSCC initiation, progression, therapeutic responsiveness, and clinical heterogeneity. This system-oriented perspective may provide a foundation for future biomarker-guided and biologically informed approaches to LSCC management.

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Cite

BibTeXRIS
BibTeX
@article{alicka2026squamous,
  title = {{Lip Squamous Cell Carcinoma: A Conceptual Framework for Integrating Molecular, Immune and Microenvironmental Drivers}},
  author = {Ylli Alicka and Skender Topi and Elona Gaxhja and Gianluca Baldini and Gino Orsini and Davide Pietropaoli and Maria Grazia Cifone and Maurizio Giuliani and Serena Altamura},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219528},
  url = {https://www.mdpi.com/1422-0067/27/21/9528},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lip Squamous Cell Carcinoma: A Conceptual Framework for Integrating Molecular, Immune and Microenvironmental Drivers
AU  - Ylli Alicka
AU  - Skender Topi
AU  - Elona Gaxhja
AU  - Gianluca Baldini
AU  - Gino Orsini
AU  - Davide Pietropaoli
AU  - Maria Grazia Cifone
AU  - Maurizio Giuliani
AU  - Serena Altamura
PY  - 2026
DA  - 2026/10/25
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219528
UR  - https://www.mdpi.com/1422-0067/27/21/9528
AB  - Lip squamous cell carcinoma (LSCC) is a distinct subtype of head and neck squamous cell carcinoma strongly associated with ultraviolet (UV) radiation exposure and characterized by unique molecular, immune, and microenvironmental features. Although UV-induced photodamage represents the principal initiating event, increasing evidence indicates that LSCC progression results from complex interactions among genetic and epigenetic alterations, dysregulated signaling pathways, chronic inflammation, immune dysregulation, host–microbiome dynamics, and tumor microenvironment (TME) remodeling. Recent advances have expanded the traditional view of LSCC by highlighting the contributions of UV-induced DNA damage, tumor protein p53 (TP53) alterations, epigenetic reprogramming, aberrant activation of key signaling pathways, and progressive immune escape mechanisms. In parallel, growing attention has focused on the role of cancer-associated fibroblasts (CAFs), stromal remodeling, microbial dysbiosis, and disruption of the microbiome–immune–metabolic axis as important modulators of disease progression and biological heterogeneity. Emerging biomarkers, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), epigenetic signatures, liquid-biopsy analytes, immune-related markers, and microbiome-associated profiles, together with artificial intelligence (AI)-based analytical approaches, are creating new opportunities for diagnosis, risk stratification, disease monitoring, and precision oncology. Rather than providing a conventional descriptive overview, this review proposes an integrated conceptual framework in which molecular, immune, microbial, and microenvironmental drivers interact through continuous bidirectional crosstalk to shape LSCC initiation, progression, therapeutic responsiveness, and clinical heterogeneity. This system-oriented perspective may provide a foundation for future biomarker-guided and biologically informed approaches to LSCC management.
SN  - 1422-0067
ER  -