Beyond density: mapping the functional landscapes of macrophage-T lymphocyte niches in the tumor microenvironment

The spatial arrangement of tumor-associated macrophages (TAMs) and T cells within distinct microanatomical niches is emerging as a key regulator of clinical outcome in solid tumors. Here, we propose a comprehensive review that integrates spatial insights with functional studies of macrophage and T cell heterogeneity, to elucidate how the physical crosstalk and the localization of these cells in the tumor microenvironment (TME) can impact the prognosis and the response to immunotherapy and, vice versa, how diverse immunotherapies can dynamically reshape the TME immune geography. We first review the heterogeneity of macrophages and tumor-infiltrating T lymphocytes (TILs) in TME, and the different types of TAM-TIL niches recently described by multidimensional proteomics and spatial transcriptomics, addressing their impact on tumor progression and response to immunotherapy. Building on our own work, we then dissect the anti-tumoral and pro-tumoral mechanisms operating in the different types of immune hubs. Next, we examine how tumor cues and therapeutic strategies can reprogram macrophages and T cells across functional and spatial dimensions, thereby promoting TME permissive to intraepithelial T cell infiltration and clinical response. Finally, we discuss how the integration of multi-omics and artificial intelligence are transitioning immuno-oncology from a cell-centric to a niche-centric paradigm, providing a roadmap for the design of next-generation therapies that precisely reprogram cellular dialogues within the tumor microenvironment.