Many epithelial cancers are still immunotherapy-resistant [1]. A feature common to epithelial cancers is the infiltration of cancer-associated fibroblasts (CAFs) as a primary component of the tumour microenvironment (TME). CAFs are non-neoplastic structural cells that expand alongside cancer epithelium, producing soluble factors and cell–cell interactions that directly support tumour growth, aggression and metastasis. With few exceptions 2, 3, 4, CAFs exert profoundly negative effects on patient survival across a range of cancers [5]. CAFs often co-localise with tumour-infiltrating T cells, and CAF signatures strongly correlate with immunotherapy resistance and poor survival, creating a strong rationale to address the impact of CAF-T-cell interactions through administration of CAF-targeted therapies. Yet, CAFs are still relatively understudied in immune-oncology clinical trials.

T cells are key mediators of anti-tumour immunity and the primary targets of approved immunotherapies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Given their potential to enact tissue damage, T-cell activation is a heavily regulated process, and fibroblasts are important, well-defined T-cell regulators in many organ systems and disease states 6, 7•, 8, 9. Many of these mechanisms are now being observed within tumours, with consequences for T-cell activation, differentiation and persistence. Yet, as we commonly observe in biology, it is complicated: high-profile clinical trial failures targeting hedgehog signalling in pancreatic cancer, paired with mechanistic mouse explorations, showed that CAFs can sometimes restrain tumour growth 2, 3, 4, 10; there are still unaddressed questions ranging from molecular mechanisms to which subsets to target.