Purpose <p>Squamous cell carcinomas (SCCs) are one of the most common cancers known to the world, which can occur at multiple locations, while they also share similarities on the genetic and epigenetic level and similar tumor microenvironment characteristics. The clinician faces a dilemma while dealing with squamous cell carcinoma; due to an average survival rate, the prognosis for recurrent/metastatic illness is very dire. Electrospun drug loaded nanofibers have emerged as an effective platform for localized therapy, enabling high drug concentration at the tumor site, which also minimizes the systemic toxicity. There are numerous studies reported for the application of nanofibers in cancer treatment, but there is a lack of comprehensive summary connecting their role across different SCC sites with respect to tumor microenvironment guided therapy and translational potential.</p> Methods <p>This review aims to consolidate evidence from in vitro and in vivo studies and to analyze how nanofiber-based drug delivery systems can strategically be utilized for various SCC types by targeting their common locoregional tumor microenvironment.</p> Results <p>Electrospun drug loaded nanofibers have emerged as an effective platform for localized therapy, enabling high drug concentration at the tumor site, which also minimizes the systemic toxicity. The review also focuses on work provided by a comparative, mechanism-oriented perspective linking genetic similarity of various SCCs, nanofiber design, influence of polymer selection, drug release behaviour, and their therapeutic efficacy.</p> Conclusion <p>Furthermore, the review also highlights the potential of nanofiber systems as minimally invasive alternatives to surgical interventions for locoregional SCC therapy. This integrated perspective aims to advance understanding of nanofiber-mediated localized therapy and guide future translational research for effective SCC treatment.</p> Graphical Abstract <p></p>