Table 3 Factors that affect PD-L1 expression

Ketogenic diet

Downregulation

TNBC and CRC

anti-CTLA-4 therapy

1. Energy stress or ketogenic diet treatment decreases PD-L1 protein abundance

2. AMPK phosphorylates PD-L1 at Ser283 to disrupt its interaction with CMTM4

3. AMPK enhances IFNs and antigen-presentation gene expression via repressing PRC2

4. AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy

[202]

Metformin

Downregulation

TNBC

anti-CTLA-4 therapy

1. Metformin enhances antitumor CTL immunity by blocking PD-L1/PD-1 axis

2. Metformin-activated AMPK directly binds to and phosphorylates PD-L1 at S195

3. Abnormal PD-L1 glycosylation induced by pS195 leads to PD-L1 degradation by ERAD

4. Combination therapy with metformin and anti-CTLA4 has a synergistic antitumor effect

[203]

Ruxolitinib

Downregulation

GBM

MV-s-NAP-uPA + anti-PD-1 therapy

1. Infection with MV-s-NAP led to PD-L1 upregulation and an increase in the levels of MHC class I molecules in glioma cells

2. Intratumoral MV-s-NAP overcomes resistance and synergizes with anti-PD1 blockade

3. Localized MV-s-NAP-uPA infection with systemic anti-PD1 blockade leverages abscopal therapeutic effect

4. Pharmacological inhibition of the JAK1/JAK2 signaling pathway with ruxolitinib improves GBM cure rates by abrogating PD-L1 expression on MDSCs

[238]

mTOR inhibitor (rapamycin)

Downregulation

NSCLC

anti-PD-1 therapy

1. The activation of AKT and mTOR is associated with PD-L1 expression in NSCLC cell lines that harbor a wide spectrum of driver mutations

2. Inhibition of PI3K, AKT or mTOR decreases PD-L1 expression in NSCLC cell lines. Rapamycin decreases PD-L1 expression in murine lung tumors

3. EGF and IFN-γ increase PD-L1 expression through activation of mTOR

4. The combination of rapamycin and a PD-1 blocking antibody decreases lung tumor growth

[175]

CSN5 inhibitor

Downregulation

TNBC

Anti-CTLA-4 therapy

1. TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation

2. Activation of NF-kB by TNF-α induces CSN5 expression that lead to PD-L1 stabilization

3. CSN5 suppresses the activities of T cell via PD-L1 deubiquitination

4. Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy

[239]

Copper-chelating drugs (Dextran–Catechin and TEPA)

Downregulation

Neuroblastoma

Not applicable

1. Copper transporter 1(CTR-1) and PD-L1 expression in cancer is positively correlated

2. Intracellular Cu levels influence PD-L1 expression in cancer cells

3. Dextran–Catechin and TEPA downregulate PD-L1 expression by inhibiting EGFR and STAT phosphorylation

4. Cu-chelation enhances infiltration of anticancer immune cells and improves the survival of mice with neuroblastoma by downregulating PD-L1

[179]

Epigallocatechin gallate (EGCG)

Downregulation

NSCLC

Not applicable

1. EGCG reduced PD-L1 expression via inhibition of the JAK2/STAT1 pathway

2. EGCG partially restored T cell activity by suppressing PD-L1/PD-1 signaling

3. Oral administration of green tea extract reduced PD-L1-positive cells and inhibited tumor growth in the lungs of NNK treated A/J mice

4. EGCG downregulation EGF-induced PD-L1 through inhibition of Akt phosphorylation in Lu99 cells

[240]

Pin1 inhibitor (ATO, ATRA, Sulfopin)

Upregulation

Pancreatic cancer

Pin1 inhibitor + anti-PD-1 antibody + gemcitabine

1. Pin1 is overexpressed in both PDAC cells and CAFs and correlates with poor prognosis of patients

2. Pin1 inhibition disrupts the desmoplastic and immunosuppressive TME by affecting CAFs

3. Pin1 inhibition upregulates PD-L1 and ENT1 expression in cancer cells by regulating HIP1R

4. Pin1 inhibition makes aggressive PDAC eradicable by synergizing with immunotherapy and chemotherapy

[241]

N⁶-methyladen-osine (M⁶A) Demethylase (ALKBH5)

Upregulation

Intrahepatic cholangiocarcinoma (ICC)

ALKBH5 inhibitor + anti-PD-1 therapy

1. PD-L1 is regulated by ALKBH5, which is a direct target of m6A modification

2. ALKBH5 deficiency promotes PD-L1 mRNA degradation

3. ALKBH5 suppresses anti-tumor T cell immunity in PD-L1-dependent manner

4. ALKBH5 and PD-L1 is positively correlated in clinical ICC specimens

[242]

Peripheral serotonin

Upregulation

CRC and pancreatic cancer

Peripheral serotonin inhibitor + anti-PD-1 therapy

1. Platelet-derived serotonin enhances growth of murine MC38 and Panc02 tumors

2. Peripheral serotonin impairs accumulation of CD8⁺ T cells within mouse tumors and dampens the function of CD8⁺ T cells

3. Serotonin promotes tumor growth in mouse models by enhancing PD-L1 expression

4. Pharmacological inhibition of serotonin dampens growth of tumors and enhances efficacy of anti-PD-1 therapy in mice

[223]

EGF/EGFR

EGF/EGFR stimulates PD-L1 glycosylation

TNBC

Drug-conjugated glycosylated-PD-L1(gPD-L1) antibody

1. N-linked glycosylation is required for interaction between PD-L1 and PD-1

2. EGF/EGFR induces PD-L1 glycosylation via B3GNT3 glycosyltransferase

3. gPD-L1 antibody stimulates PD-L1 internalization

4. gPD-L1-ADC shows potent toxicities to cancer cells and bystander effects

[243]

MYC

Upregulation

Leukemia and lymphomas

Not applicable

1. MYC regulates the expression of CD47 and PD-L1

2. Suppression of MYC in tumor cells caused reduced mRNA and protein levels of CD47 and PD-L1

3. MYC directly bind to the promoters of the CD47 and PD-L1

[94]

MUSE for MT-CRISPR/Cas9 (targeting both PD-L1 and CD47)

Downregulation

Melanoma

Not applicable

1. MUSE synergistically boosting CD8⁺ T cells and M1 macrophages-mediated adaptive and innate anticancer immunity

2. The MUSE-nano-CRISPR system showed efficient disruption efficiency of PD-L1 and CD47 in vitro and in vivo

[237]

Multispecific Platinum (IV) Complex DNP

Downregulation

Breast cancer (BC)

Not applicable

1. COX-2 plays an important role in the progression of breast cancer, correlating with the levels of PD-L1

2. DNP reduces the expression of COX-2 and PD-L1 in vitro and in vivo

3. DNP displayed potent antitumor activity and almost no general toxicity in mice bearing TNBC

[244]

Curcumin

Downregulation

HCC

anti-PD-1 therapy

1. Curcumin reduced P300-induced histone acetylation in the promoter region of TGF-β1, thereby inhibiting PD-L1 expression

2. The combination of curcumin and anti-PD-1 antibodies showed better anticancer effects in vitro and in vivo by activating lymphocytes, inhibiting immune evasion and downregulating TGF-β1 expression

[245]

TAM-targeted biomimetic nano-RBC system

Downregulation

TNBC and CRC

Not applicable

1. TAM depletion and hypoxia alleviation with TAM-targeted biomimetic nano-RBC system synergistically reprogram the immunosuppressive TME

2. This system downregulates PD-L1 expression of tumor cells, decreases immunosuppressive cytokines and increases the immunostimulatory IFN-γ and boost CTL response

[246]

Sunitinib

Downregulation

Melanoma and NSCLC

Anti-CTLA-4 therapy

1. Sunitinib modulates the expression of tumor PD-L1 via p62, which binds to PD-L1 and specifically enhances its translocation into autophagic lysosomes for degradation

2. Sunitinib showed synergistic anticancer efficacy with CTLA-4 blockade in immunocompetent mice models of melanoma and NSCLC by increasing tumor-infiltrating T cell activity

[247]