Cancer's double agents: Fibroblasts both help and hinder immunotherapy

Cancer-associated fibroblasts (CAFs) – critical but enigmatic players in tumors – exhibit "paradoxical" effects on immunotherapy, according to a new review in Clinical and Translational Discovery. While most CAFs suppress immune cells to accelerate cancer progression, certain subtypes actively restrain tumors. This duality stems from CAFs’ extreme heterogeneity, explaining why depleting all CAFs sometimes backfires by accelerating metastasis.  

CAFs sabotage immunotherapy through multiple mechanisms: remodeling the extracellular matrix into physical barriers; reprogramming immune cells (like macrophages and T cells) into pro-tumor states; and secreting immunosuppressive molecules (TGF-β, IL-6) or exosomes. Consequently, CAF-rich tumors often resist PD-1/PD-L1 inhibitors.  

Yet in specific cancers like pancreatic and breast cancer, certain CAF subtypes (e.g., αSMA+ CAFs) enhance CD8+ T-cell infiltration or restrain tumor growth. "CAFs are neither friend nor foe universally," explains senior author Dr. Peng Luo. "Their impact depends on context and subtype – precision targeting is key."  

Promisingly, therapies eliminating specific "bad" CAFs (e.g., FAP-positive subtypes) boost immunotherapy efficacy in preclinical models. Approaches include:  

- FAP-targeted CAR-T cells or vaccines  

- Blocking CAF-secreted factors (CXCL12, TGF-β)  

- Disrupting CAF-ECM remodeling  

Combining these with existing immunotherapies could overcome resistance. However, challenges remain – FAP-targeted therapies risk toxicity since healthy cells also express FAP.  

"Future success requires mapping CAF subtypes and their functions across cancer types," emphasizes Dr. Jian Zhang, co-corresponding author. "We need biomarkers to identify which patients will benefit from CAF-directed combos."