Lipid metabolic, metabolic reprogramming, immunometabolic, regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells "Cold tumors" are malignancies with poor immune infiltration and limited response to immunotherapy, largely shaped by an immunosuppressive tumor microenvironment (TME) (1-3). Lipid metabolic reprogramming has emerged as a central mechanism sustaining this suppression. Rapidly proliferating tumor cells deplete nutrients and release byproducts, generating hypoxia, acidosis, and scarcity, which force both tumor and immune cells to rewire their metabolism (4, 5). Under these stresses, not only tumor cells but also immune cells undergo "immunometabolic" reprogramming to adapt to the hostile environment (6, 7). Lipids serve as fuels, signaling mediators, and membrane components, and their altered metabolism profoundly affects immune regulation (8, 9). This mini review highlights how lipid reprogramming supports key immunosuppressive populations in the TME-regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs)-and explores therapeutic strategies that target lipid metabolism to improve cancer immunotherapy.

Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of p53 mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial p53 mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific p53 mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant p53, mice with OSCCs expressing the p53^R172H GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) p53 deletion or with wild-type p53. Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type p53 or p53 deletion, GOF p53^R172H abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the p53^R172H tumors. These findings sustain a potential role for p53 profiling in personalized oral cancer immunoprevention.