The tumor microenvironment (TME) plays a central role in cancer progression and patient outcome but remains insufficiently characterized in hematological malignancies and underrepresented populations. This work combines spatial immune profiling of healthy and neoplastic bone marrow biopsies with the analysis of more than 1,600 breast cancer samples from 10 sub-Saharan African countries using conventional and multiplex immunohistochemistry. The findings demonstrate that immune cell composition and spatial organization change during malignant transformation, are associated with genetic alterations, disease progression, and prognosis, and differ between populations with distinct genetic backgrounds and infectious exposures. These results underscore the value of spatially resolved TME analysis for understanding tumor biology and support the integration of multiplex imaging into precision pathology and personalized cancer care.