Oral squamous cell carcinoma (OSCC) is a major malignancy in South Asia, driven by betel nut/tobacco use, with 5-year survival near 50–60% and frequent recurrences reflecting its aggressive biology. Although tissue resident memory (TRM) T cells mediate innate immunity, their spatial organization and associated regulatory role of cytokine, interleukin-15 (IL-15) in the OSCC tissues and their microenvironment remain unclear.

This study aimed to map CD4⁺ and CD8⁺ T lymphocytes, and TRM markers (CD103, CD49a, CD69) across tumor and stromal compartments, to assess the regulatory role of IL-15 and CD103 associated epithelial E-cadherin interactions and build a multivariate prognostic model.

Method Eighty OSCC cases confirmed by histopathological examination. Formalin-fixed, paraffin-embedded tumor tissues (~ 1 g) from surgical resections underwent immunohistochemistry. Whole-slide digital imaging (×40) quantified CD4⁺ and CD8⁺ T lymphocytes, and TRM markers across tumor and stromal fields. Staining intensity and percent scores were generated as a composite score (0–3). Inter-observer reliability (Kendall’s τ ≥ 0.7) was verified. Associations were tested using χ²/Fisher’s exact, while survival was analyzed by Kaplan–Meier and Cox regression (HR, 95% CI).

Results Immune and epithelial marker expression varied significantly across tumor and stromal compartments (p < 0.001). Advanced tumor stage predicted poor survival (p = 0.044). Retained E-cadherin correlated with improved survival (p = 0.027), while CD49a expression was associated with adverse outcomes (p = 0.006). Multivariate Cox regression identified CD103 (Adj.HR 2.02, 95% CI 1.03–3.96) and E-cadherin (Adj.HR 3.01, 95% CI 1.25–7.23) as independent adverse predictors, whereas stromal CD8 (HR 0.35, 95% CI 0.14–0.99) and CD49a (HR 0.37, 95% CI 0.14–0.98) were protective. High IL-15 expression showed a positive association with CD103⁺ TRM T cell infiltration, particularly within the stromal compartment, although the association did not reach statistical significance (p = 0.076).

Conclusion The spatial interplay among IL-15 expression, CD103⁺ immune infiltration, and the localization of TRM-associated markers suggests the presence of an integrated immune-epithelial axis associated with OSCC progression and may provide prognostic and therapeutic insights.