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Figure 2. Mechanisms of immune resistance in tumor cells and strategies to reverse resistance. Tumors contain genotypically and phenotypically heterogeneous populations of transformed cells that develop resistance to cancer immune surveillance through innate or ongoing processes of selection by immune cells. Both the innate and the adaptive immune systems participate in an anti-tumor response that involves T cell-priming by DCs and Th1 cytokines (IL-1, IL-6, TNF-α, and IFN-γ) secreted by Th1 cells. Immune effectors infiltrating the tumor, such as CTLs, M1 macrophages, and NK cells, actively eliminate sensitive tumor cells through ADCC, phagocytosis, perforin/granzyme, or TRAIL-mediated apoptosis, whereas resistant tumor cells remain untouched and proliferate. We present five exemplary mechanisms of immune resistance and the corresponding therapies that have proven effective at reversing the alterations responsible for resistance. (1) Tumor cells modulate their expression of immunogenic ligands (e.g., NKG2DLs) and MHC class I molecules to escape detection by CTLs and NK cells. CAR T cells, engineered T cells, and small molecule inhibitors (e.g., MAPK pathway inhibitors) evoke enhanced anti-tumor activity either by acting independently of MHC class I molecules or re-upregulating tumor ligand expression. (2) Tumor cells coopt survival pathways and the anti-apoptotic proteins Bcl-2 and c-FLIP to resist immunogenic cell death via TRAIL or immune cell targeting. Anti-apoptotic inhibitors have proven effective at inhibiting these proteins and reversing the apoptosis-resistant phenotypes. (3) Immune checkpoint ligands (e.g., PD-L1 on tumor cell surfaces and CTLA-4 and PD-1 on T cell surfaces) effectively decommission anti-tumor T cells during the maturation phase of naïve T cells and during the effector/tumor-killing phase. Checkpoint inhibitors are monoclonal antibodies that can synergize with T cell-focused therapies by blocking either the coinhibitory ligand or its receptor to prevent anergy in naïve and mature T cells. (4) The dynamic TME consists of immunosuppressive immune cells (e.g., Treg cells, MDSCs, M2 macrophages, and CAFs) and factors (e.g., TGF-β, IL-10, and IL-4) that suppress anti-tumor effector cell functions and seclude them away from the tumor. Monoclonal antibodies targeted to immunosuppressive cell markers to deplete these cells or angiogenesis inhibitors that recondition the TME are able to enhance CTL activation and infiltration into the tumor. (5) AICD threatens the long-term efficacy of adoptive cell transfer therapies by depleting T cells via Fas-FasL or repetitive TCR stimulation. Previous evidence suggests that halting the conduction of the death signals in T cells by downregulating lncRNA and histone deacetylase expression can inhibit AICD and potentiate the formation of immune memory. AICD: activation-induced cell death; Bcl-2: B cell lymphoma 2; CAR: chimeric antigen receptor; c-FLIP: cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; CAF: cancer-associated fibroblasts; CTL: cytotoxic T lymphocyte (CD8+); CTLA-4: cytotoxic lymphocyte-associated protein 4; DC: dendritic cell; FasL: fas ligand; IFN-γ: interferon γ; IL-1: interleukin 1; IL-6: interleukin 6; M1: M1 macrophage; M2: M2 macrophage; MAPK: mitogen-activated protein kinase; MDSC: myeloid-derived suppressor cell; MHC-I: major histocompatibility complex class I; MHC-II: major histocompatibility complex class II; NK: natural killer cell; NKG2DL: natural killer group 2D ligand; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; TCR: T cell receptor; TGF-β: transforming growth factor-β; Th1: T helper 1 cell (CD4+); TME: tumor microenvironment; TNF-α: tumor necrosis factor α; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; Treg: T regulatory cell; ADCC: antibody-dependent cell cytotoxicity; MDSCs: myeloid-derived suppressor cells; lncRNA: long non-coding RNA