Table 1.

Mechanisms of acquired resistance and potential therapeutic approaches

Resistance mechanisms	Description of resistance mechanisms	Potential therapeutic approaches
Loss of immunogenic neoantigen	Defects in IFN-γ pathway	STING agonist, JAK inhibitor, STAT inhibitor
Upregulation of alternate immune checkpoint receptors	Compensatory upregulation of inhibitory receptors (LAG-3, TIM-3, TIGIT, BTLA, VISTA, SIGLEC9)	Blockade of alternate coinhibitory immune checkpoint receptors: LAG-3, TIM-3, TIGIT, BTLA, VISTA, SIGLEC9
		Immune stimulatory agents: OX40, ICOS
Immunosuppressive cells and immunoregulative molecules in tumor microenvironment	Increased immunosuppressive cells (Treg, MDSC, M2 macrophage)	CSF1R inhibitor, TGF-β inhibitor
	Elevated immunosuppressive cytokines (TGF-β, VEGF, IL-6/8)	TGF-β inhibitor, VEGF inhibitor, IL-1β inhibitor, IL-6/8 inhibitor
	Immunoregulative molecules: adenosine pathway, IDO1, B7-H4	A2AR inhibitor/anti-CD73, IDO inhibitor, B7-H4 inhibitor
Epigenetic modification	Tumor suppressor, apoptosis gene modification Stability of chromatin remodeling complexes	Epigenetic modulators: DNMTi, HMTi, HDACi Adoptive T cell therapy

IFN-γ, interferon-γ; STING, stimulator of IFN genes; JAK, Janus kinase; STAT, signal transducer and activators of transcription; LAG-3, lymphocyte-associated gene 3; TIM-3, T-cell immunoglobulin and mucin domain-3; TIGIT, T-cell immunoglobulin and ITIM domain; BTLA, B and T-lymphocyte attenuator; VISTA, V-domain immunoglobulin suppressor of T-cell activation; SIGLEC9, sialic acid binding Ig-like lectin 9; ICOS, inducible T-cell costimulator; Treg, regulatory T-cell; MDSC, myeloid-derived suppressor cell; CSF1R, colony stimulating factor 1 receptor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; IL, interleukin; IDO, indoleamine 2,3-dioxygenase; A2AR, adenosine A2A receptor; DNMTi, DNA methyltransferase inhibitor; HMTi, histone methyltransferase inhibitor; HDACi, histone deacetylase inhibitor.