Oral squamous cell carcinoma (OSCC) is typified by extensive stromal fibrosis and an immunosuppressive microenvironment, both of which impede effective responses to immune checkpoint blockade. In this study, we identify prolyl 3-hydroxylase family member 4 (P3H4) as a critical mediator of extracellular matrix (ECM) remodeling, epithelial–mesenchymal transition (EMT), and the exclusion of cytotoxic CD8⁺ T lymphocytes. Elevated P3H4 expression correlates with unfavorable clinical outcomes and resistance to immunotherapy. Genetic ablation of P3H4 significantly attenuates tumor progression and promotes CD8⁺ T cell infiltration. To pharmacologically target P3H4, we engineered a liposomal formulation of 1,4-dihydrophenanthroline-2,5-dicarboxylic acid (1,4-DPCA), a small-molecule prolyl hydroxylase inhibitor. This nanomedicine, designated Lipo-1,4-DPCA, effectively downregulates P3H4 expression, mitigates tumor-associated fibrosis, reprograms the immune microenvironment, and elicits robust anti-tumor responses in vivo. Collectively, our findings establish P3H4 as a promising therapeutic target and highlight Lipo-1,4-DPCA as a dual-functional nanotherapeutic candidate capable of enhancing the efficacy of immunotherapy in OSCC.