Table 1.

Putative mechanisms and approaches to overcome acquired immune checkpoint inhibitor (ICI) resistance in non-small-cell lung cancer. Most approaches have multiple potential mechanisms of actions.

Mechanisms of Acquired ICI Resistance	Potential Therapeutic Approaches
Impaired processing or presentation of tumor-associated antigens	Chemotherapy, radiotherapy, cancer vaccines, oncolytic viruses, TLR agonists
Fixed epigenetic modification of T cells	Epigenetic modulators (hypomethylating agents, histone deacetylase inhibitors)
Defects in IFN-γ pathways	STING agonists, c-di-GMP, JAK inhibitors
Upregulation of other immune checkpoints	Combination immune checkpoint inhibitors (such as CTLA-4, TIGIT, LAG-3, TIM-3, VISTA, BTLA), immune stimulatory agents (such as OX40, CD40, GITR, ICOS, 4-1BB)
Immunosuppressive cells/inhibitory metabolites in the tumor microenvironment	Macrophage inhibitors (such as CSF1R inhibitors), cytokine/chemokine inhibitors, targeted therapies targeting canonical pathways (such as against VEGF, PI3K), IDO inhibitors, TGF-β inhibitors, CXCR2 inhibitors, CXCR4 inhibitors, A2AR inhibitors/anti-CD73
Gut microbiome	Fecal microbiota transplantation, probiotics, diet interventions

ICI: Immune checkpoint inhibitors; TLR: Toll-like receptors; STING: Stimulator of interferon genes; c-di-GMP: Bis-(3′-5′)-cyclic dimeric guanosine monophosphate; JAK: Janus kinase; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; TIGIT: T cell immunoreceptor with immunoglobulin and ITIM domains; LAG-3: Lymphocyte-activation gene 3; TIM-3: T cell immunoglobulin and mucin-domain containing-3; VISTA: V-type immunoglobulin domain-containing suppressor of T cell activation; CD40: Cluster of differentiation 40; GITR: Glucocorticoid-induced TNFR-related; ICOS: Inducible T cell costimulatory; BTLA: B- and T-lymphocyte attenuator; CSF1R: Colony stimulating factor 1 receptor; VEGF: Vascular endothelial growth factor; PI3K: Phosphoinositide 3-kinases; IDO: indoleamine 2,3-dioxygenase; TGF-β: Transforming growth factor beta; CXCR2: CXC chemokine receptor 2; CXCR4: CXC chemokine receptor 4; A2AR: Adenosine A2A receptor; CD73: Ecto-5′-nucleotidase.