Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status
Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs cur...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1297175/full |
| _version_ | 1797644359483523072 |
|---|---|
| author | Lisa Schlicher Luke G. Green Andrea Romagnani Florian Renner |
| author_facet | Lisa Schlicher Luke G. Green Andrea Romagnani Florian Renner |
| author_sort | Lisa Schlicher |
| collection | DOAJ |
| description | Following the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs currently include enzymes of negative feedback loops in signaling pathways of immune cells and proteins that promote immunosuppressive signals within the tumor microenvironment. In the adaptive immune system, negative regulators of T cell receptor signaling (MAP4K1, DGKα/ζ, CBL-B, PTPN2, PTPN22, SHP1), co-receptor signaling (CBL-B) and cytokine signaling (PTPN2) have been preclinically validated as promising targets and initial clinical trials with small molecule inhibitors are underway. To enhance innate anti-tumor immune responses, inhibitory immunomodulation of cGAS/STING has been in the focus, and inhibitors of ENPP1 and TREX1 have reached the clinic. In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers. |
| first_indexed | 2024-03-11T14:29:25Z |
| format | Article |
| id | doaj.art-a95de092546d44f89ad16bface7d5304 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T14:29:25Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a95de092546d44f89ad16bface7d53042023-10-31T11:18:19ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12971751297175Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current statusLisa Schlicher0Luke G. Green1Andrea Romagnani2Florian Renner3Cancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, SwitzerlandTherapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, SwitzerlandCancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, SwitzerlandCancer Cell Targeted Therapy, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, SwitzerlandFollowing the success of cancer immunotherapy using large molecules against immune checkpoint inhibitors, the concept of using small molecules to interfere with intracellular negative regulators of anti-tumor immune responses has emerged in recent years. The main targets for small molecule drugs currently include enzymes of negative feedback loops in signaling pathways of immune cells and proteins that promote immunosuppressive signals within the tumor microenvironment. In the adaptive immune system, negative regulators of T cell receptor signaling (MAP4K1, DGKα/ζ, CBL-B, PTPN2, PTPN22, SHP1), co-receptor signaling (CBL-B) and cytokine signaling (PTPN2) have been preclinically validated as promising targets and initial clinical trials with small molecule inhibitors are underway. To enhance innate anti-tumor immune responses, inhibitory immunomodulation of cGAS/STING has been in the focus, and inhibitors of ENPP1 and TREX1 have reached the clinic. In addition, immunosuppressive signals via adenosine can be counteracted by CD39 and CD73 inhibition, while suppression via intratumoral immunosuppressive prostaglandin E can be targeted by EP2/EP4 antagonists. Here, we present the status of the most promising small molecule drug candidates for cancer immunotherapy, all residing relatively early in development, and the potential of relevant biomarkers.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1297175/fullcancer immunotherapysmall molecule inhibitorsimmuno-oncologytumor microenvironmentadenosinecGAS/STING |
| spellingShingle | Lisa Schlicher Luke G. Green Andrea Romagnani Florian Renner Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status Frontiers in Immunology cancer immunotherapy small molecule inhibitors immuno-oncology tumor microenvironment adenosine cGAS/STING |
| title | Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status |
| title_full | Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status |
| title_fullStr | Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status |
| title_full_unstemmed | Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status |
| title_short | Small molecule inhibitors for cancer immunotherapy and associated biomarkers – the current status |
| title_sort | small molecule inhibitors for cancer immunotherapy and associated biomarkers the current status |
| topic | cancer immunotherapy small molecule inhibitors immuno-oncology tumor microenvironment adenosine cGAS/STING |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1297175/full |
| work_keys_str_mv | AT lisaschlicher smallmoleculeinhibitorsforcancerimmunotherapyandassociatedbiomarkersthecurrentstatus AT lukeggreen smallmoleculeinhibitorsforcancerimmunotherapyandassociatedbiomarkersthecurrentstatus AT andrearomagnani smallmoleculeinhibitorsforcancerimmunotherapyandassociatedbiomarkersthecurrentstatus AT florianrenner smallmoleculeinhibitorsforcancerimmunotherapyandassociatedbiomarkersthecurrentstatus |