The multicellular coordination underlying tissue homeostasis and disease progression is of fundamental interest; however, the organization of diverse cell types within tissue niches for cohesive functioning remains largely unknown. Here, we systematically characterized cross-tissue coordinated cellular modules (CMs) with spatiotemporal dynamics and phenotypic associations, as well as their rewiring in cancer. We first compiled a comprehensive single-cell transcriptomic atlas from 35 human tissues, revealing considerable variability in cellular composition among tissues, including the depletion of universal fibroblasts in the reproductive system. Leveraging covariance in cellular abundance, we identified 12 CMs with distinct cellular compositions, tissue prevalences, and spatial organizations, including two immune CMs that exhibit contrasting chronological dynamics in the spleen with aging. Additionally, in situ spatial and in vivo perturbation data demonstrated coordinated multicellular communication within CMs. By analyzing coordinated multicellular changes in the breast, we identified a menopausal trajectory associated with fibroblast dynamics. Furthermore, analysis of cancerous samples across multiple cancer types uncovered both the loss of tissue-specific healthy organizations and the emergence of a convergent cancerous ecosystem during tumor progression. In summary, these findings elucidate the fundamental organizing principles of multicellular ecosystems in health and cancer, laying a foundation for further investigations into multicellular dynamics across diverse contexts, including cellular regulation, tissue regeneration, and disease intervention.

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