Abstract
Mesenchymal Stromal Cells (MSCs) and pericytes, although a minor cellular component of the tumor microenvironment (TME), exert outsized control over cancer progression, metastasis, and therapeutic response across both solid and hematologic malignancies. Once separated by functional and anatomical criteria, Single-cell RNA sequencing (scRNA seq) analyses and context-dependent phenotypic transitions - pericyte-to Cancer-Associated Fibroblasts (CAFs) and MSCs-to-CAFs, now blur these classical distinctions, revealing fluid entities and substantial functional convergence. We synthesize current evidence showing that MSCs and pericytes frequently adopt overlapping pro-angiogenic, immunosuppressive, and pro-invasive states driven by PDGF-B/PDGFRβ, TGF-β, CXCL12, and Notch/ROCK signaling. Across cancers, their roles are multifaceted: in Colorectal Cancer (CRC) from neo-vascularization and Drug Resistance (DR) to blood vessel formation, invasion, and metastatic spread. Moreover, MSCs reinforce immunosuppression, whereas pericyte phenotype switching may sensitize tumors to immunotherapy, thus playing a pivotal role in fibrosis-driven cancer progression. In hematologic malignancies, particularly in the Bone Marrow (BM) niche, MSCs sustain leukemic cell survival and DR. Shared markers and transcriptomic signatures, coupled with striking plasticity, underscore their central role in shaping a pro-tumorigenic milieu. This convergence helps to explain the limits of current approaches-such as anti-VEGF monotherapy and supports new strategies. Enhancing pericyte maturity or intercepting transitions toward CAFs are promising avenues to boost treatment efficacy. We propose a practical framework for classifying "MSC-pericyte states" in the TME and emphasize rigorous, multi-marker, spatially resolved analyses to dissect their complex functions, thus opening a new scenario for targeted therapies.