Table 1.
Main endosomal TLR agonists, biological and antitumor effects, and examples of combinations of TLR-TLRag and TLR-STINGag.
| TLR | Ligand | Cancer and Model | Observations | References |
|---|---|---|---|---|
| TLR3 | Poly(I:C) | Syngeneic animal models and clinical trials | High antitumoral efficacy in several preclinical models; clinical trials were not successful | [54,55,62,66,67] |
| Poly-ICLC (hiltonol®) | Syngeneic animal models and clinical trials | Pharmaceutical formulation is more stable than poly(I:C) and more effective but highly toxic | [53] | |
| Poly(A:U) | B16.F10-OVA melanoma murine model | Antitumoral efficacy, activation of DCs, increase in CD8+ T cell infiltration, and decrease in IL-10-producing M2-like macrophages | [56] | |
| TLR7/8 | R837 (imiquimod®) |
FDA-approved for the treatment of basal cell carcinomas | Promotes apoptosis and cell-mediated antitumor immunity | [9,64,67] |
| R848 (resiquimod®) |
MC38 colon cancer and B16.F10 melanoma murine models, orthotopic model of NSCLC | Complete tumor regression, preventing tumor growth after re-challenge | [58,59] | |
| Clinical trials in hematological neoplasias and solid tumors | Controversial results related to poor antitumoral activity and immunotoxic effects | [42], reviewed in [47] | ||
| 1V199, 1V270 | B16cOVA murine model | Inhibition of tumor growth when low repeated doses were used | [61] | |
| TLR9 | CpGnt | Syngeneic animal models and clinical trials | Activate pDCs and CTLs, enhancing T cell-mediated antitumor immunity; in clinical trials, short half-life in serum leading to low activation of NK cells and CTLs, and increase of pro-inflammatory cytokine production | [62], Reviewed in [45] |
| TLR3 + TLR7/8 | Poly(I:C) + R848 | Lung adenocarcinoma and fibrosarcoma murine models | Antitumoral activity mainly driven by macrophage reprogramming, which promoted the activation of innate and adaptive immune responses against the cancer cells | [63] |
| Lymphoma murine models | Profound antitumor effects in the context of peptide vaccination | [73] | ||
| Poly(I:C) + R837 | B16.F10(OVA) melanoma murine model | Synergistic activation of antitumor immune responses and direct killing of cancer cells in established tumors | [72] | |
| TLR3 + TLR9 | Poly(I:C) + CpGnt | Murine glioma model | Inhibition of tumor growth and improved median survival, by activation of an antitumor phenotype of microglia | [68] |
| TLR7/8 + TLR9 | 3M-052 + CpGnt | Colon carcinoma murine model | Upregulation of Th1 cytokine-expression, reduction in the number of tumor resident MDSCs, increasing in the accumulation of NK cells and CD8+ T lymphocytes, leading to strong and long-lasting antitumoral immune responses | [69] |
| TLR4 + TLR7/8 | HMGB1 + R848 | CT26 murine tumor model | Increased the infiltration of T cells and activation and homing of tumor-infiltrating DCs to the draining lymph node, eradication of large established tumors and resistance to re-challenge | [70] |
| TLR2/6 + TLR 7/8 | Pam2CSK4C + azide | B16.F10 melanoma murine model | CD8+ T cell and NK cell antitumor responses, inhibits tumor growth and reduced adverse effects | [71] |
| TLRs + STING agonists | CpGnt + cGAMP | EG-7 and B16 F10 murine tumor models | Synergistic activation of NK cells, resulting in high production of IFN-γ and activation of CD8+ T cell response in vivo | [74] |
| Poly(I:C)-nanocomplex (BO-112®) + DMXAA |
Colon cancer and melanoma murine models | Strong antitumoral activity and abscopal effect, while none of the single drugs showed such an activity | [75] |