This research identifies transforming growth factor β (TGFβ) as a major obstacle to the formation of tertiary lymphoid structures (TLSs) in pancreatic cancer. While lymphotoxin beta receptor (LTBR) signaling can trigger the development of these immune aggregates, high levels of TGFβ program fibroblasts into a myofibroblastic (myCAF) state that suppresses immune cell recruitment. By inhibiting the TGFβ receptor, researchers successfully transitioned these cells into reticular CAFs (rCAFs), which secrete the chemokines necessary to draw in T and B cells. This reprogramming converted TLS-resistant tumors into TLS-permissive environments, significantly improving immune-mediated tumor control. The study also confirms that in human patients, rCAFs are found near protective lymphoid structures while myCAFs remain distant, suggesting that targeting this cellular switch could enhance immunotherapy for resistant solid tumors.

References:

• Kirschstein E, Harder O, Krull J, et al. Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer[J]. Cancer Cell, 2026.