Table 1.
Potential combination strategies to improve the antitumor effect of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 blockade.
| Targeted process | Strategy | Mechanisms | Reference |
|---|---|---|---|
| Releasing tumor antigens | Radiotherapy | Promoting the release of immunogenic neoantigens | (134) |
| Chemotherapy | Inducing the ICD | (14) | |
| Oncolytic viruses | Promoting tumor ICD and “in situ” vaccination | (135) | |
| Enhancing antigen presentation | Histone deacetylase inhibitors | Epigenetically modulating the upregulation of the MHC pathway | (136) |
| DNMTi | Elevating the expression of several antigen-presenting molecules | (137) | |
| STING agonists | Activating cGAS-STING to reverse MHC-I downregulation | (138) | |
| Polyinosinic:polycytidylic acid (poly I:C) | Inducing MHC I expression via NF-κB | (139) | |
| TLR9 agonists | Augmenting conventional DC (cDC) infiltration to increase antigen delivery | (140) | |
| Flt3L-poly I:C combined injection | Upregulating the expression levels of CD86, CD40, and MHC II of tumor-infiltrating CD103+ DC | (141) | |
| Promoting T-cell infiltration | PI3K-AKT pathway inhibitors | Promoting T-cell infiltration in PTEN loss melanoma | (142) |
| Reversing T-cell exhaustion | PORCN inhibitors CGX-1321 | Suppressing Wnt/β-catenin signaling to improve CD8+ T-cell levels | (143) |
| MEK inhibitors | Inhibiting the MAPK signaling pathway to increase T-cell infiltration | (144) | |
| CDK4/6 inhibitor abemaciclib | Increasing T-cell recruitment with elevated levels of TH1 cytokines/chemokines | (145) | |
| TGF-β inhibitors | Inducing potent and durable cytotoxic T-cell responses | (146) | |
| Antiangiogenic therapies | Elevating the expression of adhesion molecules, facilitating the adhesion and extravasation of T cells | (147) | |
| Low-dose radiotherapy | Reprogramming the TME and inducing T-cell infiltration | (148) | |
| Mesoporous silica nanoparticle | Eliciting T-cell-recruitment chemokine production and driving CTL infiltration | (149) | |
| CAR T therapy | Directly providing antigen-sensitive immune infiltration | (150) | |
| Dual checkpoint inhibitors | Blocking the alternative immune checkpoints to reverse T-cell exhaustion | (151) | |
| Costimulatory agonists | Reversing T-cell exhaustion and inducing the increase of effector CD8+ T cells | (152) | |
| Targeting transcriptional regulator TOX | Downregulating TOX to ameliorate the exhaustion state of CD8+ T cells | (153) | |
| DNMTi | Epigenetically inducing the rejuvenation of exhausted CD8+ T cells | (154) | |
| Metabolic modulation | Instructing T-cell metabolic programming | (155) | |
| CD8+ T-cell stimulation | Targeting TGF-β | Reducing tumor-infiltrating Tregs | (156) |
| CSF1R inhibitors | Inhibiting the differentiation and accumulation of M2-like TAMs | (157) | |
| Carflzomib | Reprogramming M2 macrophages into the M1-like population through IRE1a-TRAF2-NF-κB signaling | (158) | |
| NOX4 inhibitors | Reversing TGF-β1-mediated CAF activation | (159) | |
| Radiotherapy | Increasing CD8+ T cells with the reduction of MDSCs and Tregs | (160) | |
| Microbiota-centered interventions | Regulating the collaboration of microbiota with the TME to promote antitumor T-cell responses | (161) |
ICD, immunogenic cell death; MAPK, mitogen-activated protein kinase; DNMTi, DNA methyltransferase inhibitors; NOX4, NADPH oxidase-4.