Spatially organized macrophage–T-cell crosstalk in cervical cancer: insights from single-cell and spatial omics

Abstract

Immunotherapy has transformed the therapeutic landscape of advanced cervical cancer, yet clinical benefit remains limited by a highly heterogeneous and immunosuppressive tumor microenvironment. Traditional paradigms, including binary M1/M2 macrophage polarization and models that interpret T-cell dysfunction solely through checkpoint expression, are insufficient to capture the localized intercellular dynamics that drive immune evasion. Recent advances in single-cell and spatial multi-omics have fundamentally reshaped our understanding of this landscape. In this review, we synthesize emerging high-dimensional atlases to reframe macrophage–T-cell crosstalk from simple ligand–receptor interactions into a spatially organized ecological model. We highlight the paradigm shift toward highly resolved myeloid programs, particularly SPP1+ and C1QC+ macrophage states, and discuss how these programs interact with stromal barriers, regulatory T cells, and metabolic checkpoints to restrict, exclude, or functionally constrain effector T cells within suppressive niches. Crucially, we position persistent high-risk human papillomavirus infection not merely as an initiating carcinogenic trigger, but as an upstream and continuous programmer that rewires innate immune sensing, including context-dependent cGAS–STING-related circuits, to stabilize local immune tolerance throughout disease progression. Finally, we propose translational strategies for distilling complex multi-omic atlases into pathology-compatible prognostic and predictive biomarker signatures. Ultimately, by deciphering these spatially organized networks, this review aims to provide actionable translational insights for targeting macrophage vulnerabilities, guiding biomarker-driven combinatorial immunotherapies, and overcoming immune resistance in cervical cancer.