Background: Colon cancer (CRC) is one of the most prevalent malignancies worldwide and is strongly associated with obesity and chronic inflammation, both of which are influenced by lifestyle factors, particularly dietary habits. Technological advances in food processing and availability have increased the consumption of hypercaloric diets, leading to excessive caloric intake and lipid accumulation within cells. This accumulation interferes with metabolic pathways linked to poor tumor prognosis. In cancer cells, altered lipid metabolism involves the modulation of key metabolic regulators. Lipid droplets (LD) are lipid-rich, cytoplasmic organelles that play important roles in cell signaling, lipid metabolism, and the production of inflammatory mediators. LD biogenesis is a regulated process, and accumulation of these organelles is a frequently observed in several pathogenic situations, including inflammation and in different neoplastic processes. However, it is not clear whether LD accumulation is directly involved in the cancer cell development. Objectives and Methods: This study investigated how distinct dietary patterns influence LD profiles and frequencies during tumor progression. C57BL/6J mice were fed for 12 weeks with one of three diets: a standard Chow (Control), a high-fat/high-sucrose diet (HFHS), or a fast-food mimicking diet (FFMD). Colorectal carcinogenesis was subsequently induced using azoxymethane (AOM) followed by three cycles of dextran sulfate sodium (DSS). In parallel, the metabolic responses of non-tumor intestinal cells (IEC-6) and three CRC cell lines (LoVo, HT29, and Caco-2) were evaluated in vitro following oleate and palmitate treatment. Assessments included cell viability, LD immunofluorescence, ATP quantification, and ROS production. Results: Despite lower total caloric intake, mice on HFHS and FFMD diets exhibited significant weight gain, visceral adiposity, hepatic steatosis, and insulin resistance compared to the Chow group, been these effects more pronounced in males. While the AOM/DSS protocol induced tumors across all groups, high-calorie diets, specifically FFM, significantly increased tumor burden and mortality. Mortality was notably higher in males across all dietary interventions, probably due to a higher frequency of distal colon tumors which frequently led to rectal prolapse. Furthermore, while total B and T cell frequencies in mesenteric lymph nodes remained stable, the hypercaloric diets altered activation profiles of CD4? and CD8? T cells. These sex-dependent changes were characterized by increased expression of exhaustion markers PD-1, Tim-3, and Lag-3 on CD8? T cells. In vitro, Caco-2 cells demonstrated superior metabolic flexibility, showing the highest proliferative activity and a rapid expansion of LD at 24h, followed by efficient lipid utilization. In contrast, IEC-6, LoVo, and HT29 cells accumulated LD but failed to metabolize them effectively, suggesting a limited capacity to harness lipids for energy production. Conclusions and Implications: Our findings demonstrate that diet composition and sex exert distinct influences on immune exhaustion and metabolic reprogramming during colorectal tumorigenesis. The differential ability of tumor cells to utilize LD highlights lipid metabolism as a critical factor in cancer progression. These data suggest that LD may serve as both biomarkers for disease progression and novel therapeutic targets in anti-cancer strategies.