Tumors are complex and dynamic ecosystems comprised of multiple cell populations that co-evolve over the course of disease [1]. As such, in addition to malignant cancer cells, the TME contains CAFs, innate and adaptive immune cells, blood vessels and lymphatic vessels, intratumoral microbes, nerves, and tertiary lymphoid structures [1, 2, 3, 4]. To add to the complexity, cancer and TME cells secrete extracellular matrix (ECM), soluble proteins, extracellular vesicles (EVs), and metabolites, which altogether establish local and systemic intercellular communication networks [1,5] (Figure 1). The TME also contains regions of hypoxia, high interstitial fluid pressure, acidosis, and elevated stiffness, which altogether foster tumor progression [6,7]. It is worth noting that the presence and the prevalence of each component described here vary across cancer types, individuals, primary and metastatic sites, course of disease, and in response to therapies, underscoring the need for a personalized approach to understand and treat cancer.

In response to tissue damage or tumor-derived signals, quiescent fibroblasts acquire an activated state and are called myofibroblasts or CAFs. Of note, CAFs not only originate from resident fibroblasts but also from adipocytes, pericytes, endothelial cells (ECs), mesothelial cells, and mesenchymal stem cells (MSCs) [5,8,9]. The proteins α smooth muscle actin (αSMA), fibroblast activation protein (FAP), fibroblast-specific protein 1 (FSP1), platelet-derived growth factor receptor α (PDGFRα) and PDGFRβ are typically used as CAF markers [5,8,9]. During the activation process, CAFs acquire an enhanced ability to produce and remodel the ECM, become hyperproliferative and hypersecretory, stimulate the formation of new blood vessels, and recruit immune cells. CAFs display exceptional plasticity and exist in a spectrum of functional states that can either promote [10•, 11, 12•] or restrain [13, 14, 15] tumor progression via modulation of cancer cells and various TME cell populations [5,8,9,16,17]. For an in-depth overview of the current understanding of CAF heterogeneity in cancer, please refer to recent reviews [16,17].