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In the era where immunotherapy is emerging as a pillar for cancer therapy, tumor heterogeneity represents a hidden barrier to clinical success of immuno-oncotherapy. The heterotypic interactions between cancer cells and the immune cells provide a complex dynamic platform that significantly impacts tumor progression and subsequent response to treatment (1, 2). The reciprocal interplay is influenced by local alterations, including different regional stiffness, co-existing vascularized and hypoxic areas, spatial genotype differences, and different distribution of immune cells. Cancer cells are capable of immune escape from both innate and adaptive immune cells (3). The immune checkpoints have certainly been novel therapeutic targets to generate robust anti-tumor immune responses and have emerged as a prominent choice of cancer therapy (4). Yet, the benefit of immune checkpoint inhibitors (ICIs) has been demonstrated only in a small subgroup of cancer patients (5). In solid tumors, one of the major reasons for not obtaining an optimal response from the ICIs has been ascribed to the spatial heterogeneity of the tumor microenvironment (TME), due to the remodeling of the intrinsic tissue architecture that dramatically affects the distribution of tumor-infiltrating immune cells. This spatial heterogeneity leads to varying degrees of cancer immune escape phenomena resulting in partial or no response to ICIs or acquired resistance (6, 7). Hence, analysis of the TME and identifying factors affecting TME heterogeneity provides a promising source to develop immunotherapy biomarkers and design strategies to overcome acquired resistance to …