Cancer‐associated fibroblast heterogeneity across solid and haematological malignancies: Lessons from colorectal cancer and multiple myeloma

Abstract Although substantial advances have been made in cancer immunotherapy, the immunosuppressive tumour microenvironment (TME) continues to pose a significant obstacle to the achievement of sustained clinical responses. Cancer‐associated fibroblasts (CAFs) are increasingly recognised as pivotal regulators in the TME. Their functional adaptability shapes immune responses through extracellular matrix (ECM) remodelling, metabolic reprogramming and the secretion of immunomodulatory factors. This review explores the heterogeneity and plasticity of CAFs, characterising them as dynamic functional states, including myofibroblastic (myCAF), inflammatory (iCAF), antigen‐presenting (apCAF) phenotypes and hypoxia‐induced senescent fibroblasts (hsCAF), which transition fluidly in response to microenvironmental cues and oncogenic signalling. Through a comparative analysis of colorectal cancer (CRC) and multiple myeloma (MM), this review highlights how stromal regulation is adaptive across solid and haematological malignancies. In CRC, CAFs establish dense, collagen‐rich ECM barriers that exclude effector T cells, whereas, in MM, they establish adhesion‐dependent niches within the bone marrow to spatially segregate immune cells from malignant plasma cells. This review also discusses how oncogenic drivers such as KRAS and TP53 ‘educate’ the stromal microenvironment and explores emerging immune evasion mechanisms, including the sialic acid‐Siglec glyco‐immune checkpoint. Current therapeutic approaches are shifting from non‐selective stromal depletion toward normalising phenotypes, blocking secretome factors and disrupting metabolic interactions. The integration of spatial multi‐omics and artificial intelligence provides a framework for mapping these functional landscapes. In conclusion, harnessing CAF heterogeneity in multimodal combination therapies may help shift the tumour microenvironment from an immunosuppressive to a more pro‐immune state. image