Table 4.
Diverse designed drugs that potentially target CAF-associated effector molecules, signaling pathways and matrix proteins
| Drugs | Mechanisms | Combination therapy | therapeutic effects | Cancer models | Status | Refs |
|---|---|---|---|---|---|---|
| All-trans retinoic acid (ATRA) | Retinol levels restoration, PSC de-activation | None | Increases T-cell infiltration and Inhibits tumor growth and invasion | PDAC | Preclinical | [312] |
| Galunisertib | TGF-βR1 inhibition | Gemcitabine | Prolongs patients’ survival with minimal added toxicity | Pancreatic and hepatocellular cancer | Phase II | [313, 314] |
| Anti-CTLA4- TGF-βR2/Anti-PD-L1-TGF-βR2 | TGF-βR2 and immune checkpoints inhibition | None | Decreases tumor-infiltrating Tregs and suppresses tumor progression | Breast cancer | Preclinical | [315] |
| Tocilizumab (monoclonal antibody) | IL-6-JAK/STAT3 signaling pathway inhibition | Carboplatin/Doxorubicin | Enhances antitumor immunity and provides survival benefits | Recurrent epithelial ovarian cancer | Phase I | [316] |
| CCX872 | CCL2-CCR2 signaling axis inhibition | FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin) | Restricts immune suppression and improves clinical prognosis | Pancreatic cancer | Phase I | [317, 318] |
| AMD3100 | CCR4 inhibition | Anti-PD-L1 therapy | Promotes T-cell accumulation and eliminates cancer cells | Pancreatic cancer | Preclinical | [114] |
| F16-IL-2 | Tenascin-C depletion and IL-2 delivery | Paclitaxel/ Doxorubicin | Enhances antitumor immunity and inhibits tumor growth | Breast cancer | Preclinical | [319] |
| VS-4718 (FAK inhibitor) | FAK-targeted inhibition | Anti-PD-1 therapy | Inhibits the infiltration of immuno-suppressive cells and improves survival | Non-small-cell lung cancer, mesothelioma and pancreatic neoplasms | Phase I | [320] |
| anti-TNC dsRNA (ATN-RNA) | Tenascin-C mRNA-targeted interference | Surgery | Prolongs patients’ survival and restricts tumor recurrence | Brain glioblastoma multiforme | Phase I | [321] |
| PEGPH20 | Tumor stromal hyaluronan-targeted depletion | Gemcitabine and nab-paclitaxel | Prolongs patients’ survival with less systematic side effect | PDAC | Phase III | [322] |
| Losartan (angiotensin inhibitor) | Profibrotic signals inhibition | None | Facilitates drugs delivery and restricts ECM remodeling | Pancreatic and breast cancer | Preclinical | [323] |
Diverse strategies in CAF-targeted immunotherapies that suppress CAF activation and function and restrict ECM remodeling
CAF cancer-associated fibroblast, PSC pancreatic stellate cell, PDAC pancreatic ductal adenocarcinoma, TGF-βR1 transforming growth factor beta receptor 1, TGF-βR2 transforming growth factor beta receptor 2, CTLA-4 cytotoxic lymphocyte-associated antigen-4, PD-L1 programmed death ligand 1, IL-6 interleukin-6, JAK Janus kinase, STAT3 signal transducer and activator of transcription 3, CCX872 one of CCR2 antagonists, CCL2 C–C chemokine ligand 2, CCR2 C–C chemokine receptor 2, AMD3100 one of CXCR4 antagonists, CCR4 C–C chemokine receptor 4, IL-2 interleukin-2, FAK focal adhesion kinase, PD-1 programmed cell death protein 1, TNC tenascin-C, PEGPH20 a PEGylated human recombinant PH20 hyaluronidase, ECM extracellular matrix