Primary tumors are abnormally developed and dysregulated organs that comprise a unique ecosystem. Disseminated and metastatic cancers represent a systemic disease that often reflects the macro- and microenvironments of the ‘soil’ organs. In both settings, in addition to malignant cells, there are myriad of non-cancer cells that are inter-mingled with and frequently overshadow the tumor parenchyma. These include stromal cells (different subtypes of fibroblasts, smooth muscle cells, myofibroblasts), immune and inflammatory cells (both innate and adaptive), vasculature cells (blood vessel endothelial cells, pericytes, lymphatic and glymphatic endothelial cells), neuronal and neural cells and nerves. These non-malignant cells constitute the so-called tumor micro-environment or TME, and they constantly cross-talk to cancer cells during progression and therapies and play intricate roles in developing treatment resistance and mediating cancer relapse. Strikingly, the tumor ecosystem also exhibits sex- and aging-associated differences and dynamics. Technical advances in the past decade, especially single-cell multi-Omics (e.g., scRNA-seq, scATAC-seq, snRNA-/ATAC-seq), spatial Omics (spatial transcriptomics and spatial proteomics), and multi-spectral imaging platforms (e.g., IMC, Vectra, Phenocycler), have generated unprecedented details about the cellular (and extracellular) compositions of the tumor ecosystem, and have identified numerous novel therapeutic targets. In this Special Issue with a broad theme “Dissecting and Targeting the Heterogeneity and Plasticity of the Tumor Ecosystem”, we have collected manuscripts (Reviews, Perspectives, Research Articles) that:

• Report the heterogeneity and plasticity of cancer cell subpopulations as well as non-cancer cell types including stromal, neural and immune/inflammatory cells

• Elucidate evolutionary dynamics of and interactions/relationships between cancer cell and stromal/immune cell subpopulations

• Dissect molecular, transcriptomic, epigenetic/epigenomic, and cellular mechanisms driving the cellular plasticity and cell state transitions in both cancer and non-cancer cell compartments

• Report and dissect the heterogeneity of extracellular and systemic factors in cancer patients including (but not limited to) CTCs, cfDNAs, ctDNAs, and EVs

• Demonstrate how the cellular heterogeneity and plasticity impact and promote cancer progression, therapeutic resistance, and metastasis

• Expound on sex and aging as important biological variables associated with and driving the evolution of cancer ecosystem

• Develop and summarize novel therapeutic strategies, particularly immunotherapeutic approaches (e.g., BsAb, ADC, BiTE, CAR-T), that aim to target the cancer ecosystem including the tumor immune microenvironment.

We hope that you will be as excited as we are reading through these timely papers!