Immune cells are crucial for recognizing and suppressing cancers in the body. Unfortunately, melanomas, one of the most lethal skin cancers, can interact with and inactivate immune cells. Among the most effective anti- melanoma therapies are “immunotherapies” that “reactivate” or “train” the tumor-suppressing activities of immune cells. However, responsiveness/durations of responses are limited to subsets of patients. Although the underlying causes are unclear, lack of responsiveness is associated with insufficient infiltration of tumors by immune cells. Elucidation of melanoma:immune interactions is required to improve immunotherapies. We discovered a way to boost infiltration of melanomas with tumor-suppressing immune cells using the plant sugar L-fucose. In a cellular process called “fucosylation”, L-fucose is used to modify proteins, affecting their maturation/function. We found that fucosylation is generally reduced during melanoma progression in humans, prompting us to test if boosting L-fucose/fucosylation levels in melanomas elicits therapeutically beneficial effects. Simply feeding L-fucose to melanoma-bearing mice reduces tumor growth and metastasis by >50% (Lau et al. Sci Signal 2015). Intriguingly, those smaller tumors contain 10-50 times more tumor- infiltrating lymphocytes (“TIL”) than tumors from mice not fed L-fucose. We determined that CD4+/CD25- T cells are crucial for L-fucose-triggered recruitment of TILs including CD8+ T, NK, and DCs that suppress tumor growth. Genetic manipulation to increase fucosylation of melanoma cells elicits the same effects, suggesting that melanoma fucosylation triggers anti-tumor immunity. We identified the immune-regulating protein HLA- DRB1 as fucosylated and crucial for tumor suppression. These findings prompted our hypothesis that fucosylation of HLA-DRB1 triggers CD4+/CD25- T cell-mediated TIL recruitment and suppression of melanoma. •Specific Aim 1: Using syngeneic mouse models and de-identified patient-matched TIL/tumor cells, assess the roles and altered activation of CD4+/CD25- T cells in L-fucose-triggered melanoma suppression. •Specific Aim 2: Determine how fucosylation affects HLA-DRB1 protein behavior/function in vitro and L- fucose-stimulated tumor suppression in vivo. •Specific Aim 3: Determine how L-fucose can be administered to enhance melanoma immunotherapies (e.g., Nivolumab/Ipilumumab/TIL therapy) in mouse models. Define clinical correlations and diagnostic/prognostic potential of tumor fucosylation and fucosylated HLA-DRB1 in immunotherapy-treated patient specimens. Our goal is to elucidate how the HLA-DRB1 fucosylation regulates melanoma:immune cell interactions to improve immunotherapies and develop novel biomarkers for patient stratification for immunotherapies.