Obesity and its accompanying comorbidities, including cancer, are rising worldwide. Obesity is caused by a prolonged state of the high caloric consumption and the low energy spending, which is accompanied by long-term state of chronic inflammation of adipose tissue (AT) that leads to metabolic dysfunctions and insulin resistance. Lately, the researchers have investigated the alterations of AT in obesity to explore their roles in cancer occurrence and progression in order to answer the question of why obesity is considered a risk factor for cancer occurrence and progress. A broad variety of immune cell types found in the adipose tissue maintains the metabolic homeostasis through a carefully balanced combination of pro- versus anti-inflammatory cascades. Obesity allows expansion and infiltration of proinflammatory cells within the adipose tissue microenvironment (ATM) that aggravate the metabolic dysfunction. The lipid-rich milieu in obesity has now been proven to disrupt the intracellular metabolism of immunological cells within ATM. However, the interplay between immune cells and adipocytes in obesity status and the effects of their cross talks in driving cancer development, progress, metastasis, or therapeutic response have not been fully elucidated. Therefore, interpreting the pathophysiological and immunological changes in obesity is still a distinct challenge in oncology research. In this chapter, we will summarize the cross talk of immunological system in the setting of obesity and cancer that may potentially impact the cancer therapy.