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Tackling molecular targets beyond PD-1/PD-L1: Novel approaches to boost patients' response to cancer immunotherapy
1Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Abstract:
In the new era of immunotherapy, which has changed the clinical oncology practice guidelines, there is a pressing need for finding novel approaches to tune up the clinical outcomes of immunotherapy and extend its benefits to a wider cohort of cancer patients. Several non-classical molecular immune targets beyond PD-1/PD-L1 signaling were shown to be engaged as feedback resistance circuits to shut down the antitumor immune response mediated by the classical immune checkpoint inhibitors. Those include T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA), cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs) and OX-40 (CD134). Herein we critically discussed the latest studies concerned with understanding the mechanisms involved in the negative clinical response to classical immunotherapies and strategies to optimize the efficacy of cancer immunotherapy through novel combinatorial approaches.
Insights
New cancer immunotherapies face resistance from non-classical immune targets like ICOS and VISTA. This review explores strategies to overcome these barriers and improve immunotherapy effectiveness for more patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immunotherapy has revolutionized cancer treatment, but many patients do not respond or develop resistance.
- Resistance mechanisms often involve non-classical immune targets that suppress antitumor responses, bypassing PD-1/PD-L1 pathways.
Purpose of the Study:
- To review recent research on mechanisms of resistance to cancer immunotherapy.
- To discuss novel strategies for optimizing immunotherapy efficacy by targeting non-classical immune pathways.
Main Methods:
- Literature review of recent studies on immunotherapy resistance.
- Analysis of molecular mechanisms involving targets such as ICOS, CD40, CD47, VISTA, CDK12, EZH2, TLRs, and OX-40.
- Discussion of combinatorial therapeutic approaches.
Main Results:
- Several non-classical immune targets (ICOS, CD40, CD47, VISTA, CDK12, EZH2, TLRs, OX-40) act as resistance circuits against current immunotherapies.
- Understanding these feedback loops is crucial for predicting and overcoming treatment failure.
- Novel combinatorial strategies targeting these pathways show promise for enhancing antitumor immunity.
Conclusions:
- Overcoming resistance to cancer immunotherapy requires targeting a broader range of immune modulators beyond PD-1/PD-L1.
- Exploring novel targets and combinatorial approaches is essential to extend immunotherapy benefits to a wider patient population.
- Further research into these non-classical pathways will pave the way for more effective cancer treatments.