Hepatocellular carcinoma (HCC) is a fatal malignancy originating in hepatocytes (1). HCC accounts for 90% of primary liver cancers (2), whereby 850,000 new cases of HCC and 745,500 mortalities are annually reported worldwide (3). In China, there are nearly 466,000 new cases of HCC and 422,000 mortalities per year (4), and only 10–15% of patients meet conditions for surgical excision due to the severity of HCC (5). In advanced HCC, surgical treatment becomes infeasible due to the spread of the tumor beyond the liver. The current recommended treatment strategy in advanced disease is transarterial chemoembolization (TACE); however, most patients with HCC have primary or acquired drug resistance, which affects the efficacy of TACE (6). Thus, it is important to identify chemotherapeutic drugs aimed at novel targets to ameliorate chemotherapeutic resistance.

Immune blockade inhibitors, also known as immune checkpoint inhibitors (ICIs), are a novel type of monoclonal antibody drug that can inhibit the function of inhibitory immune receptors to evoke an immune antineoplastic response (7). In principle, this interaction can be used to treat different types of cancer, including lung cancer, melanoma, urothelial and renal carcinomas, Hodgkin's lymphoma and gastrointestinal cancers (8). Several clinical trials have investigated the potential of similar treatments for HCC (9). The efficacy of single drugs is limited, and various clinical trials are investigating the potential combination of different ICIs or the combination of ICIs and target agents (7).

Amongst the numerous checkpoint molecules, the most widely studied, and those with the greatest clinical implications in human cancer, are cytotoxicity T lymphocyte protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) (9). PD-L1 is expressed on immune cells and tumor cells, and tumor cells use PD-L1 to bind to PD-1 of T cells to ‘cheat’ the T cells and escape recognition, enabling them to continue to spread in the body. PD-L1/PD-1 antibodies can help T cells to evade this strategy and retain their ability to identify and kill tumor cells (10).

The present review discusses recent progress in clinical outcomes and influencing factors of PD-1/PD-L1 inhibitors, providing references and inspirations for the treatment of HCC.

The National Comprehensive Cancer Network (NCCN) guidelines (2019) on HCC recommend sorafinib [Child-Pugh A (Class 1 evidence) or B7] and lenvatinib (Child-Pugh A only) for first-line systematic therapy. Another targeted drug that can be used for first-line treatment is linifanib. The objective response rate (ORR) of linifanib is higher than that of solafinib; however, no significant difference between the survival rates achieved by these drugs has been observed, thus, the guide does not recommend the use of linifanib (11). A total of two drugs were recommended in the guidelines (2019) as second-line treatments, namely nivolumab and pembrolizaumab (11).

Recently, several countries, including China, have focused research on PD-1/PD-L1 inhibitors to develop novel drugs (41–45). Chinese companies, such as Junshi Bioscience, Xinda Bioscience and Hengrui Medicine aim to compete with Bristol-Myers Squibb, Merck & Co., Inc. and other famous pharmaceutical enterprises. Although there is a long process from research to improvement in clinical outcomes, Chinese pharmaceutical companies hope to see patients benefit from their efforts.

On June 15, 2018, the China CFDA approved the listing of the nivolumab injection, which was the first PD-1 receptor blocker to be approved for marketing in China. Pembrolizaumab entered the Chinese market shortly afterwards as a second-line option for HCC therapy, along with nivolumab. To advance the development of tumor immunotherapy, Chinese pharmaceutical companies have also independently developed new PD-1/PD-L1 inhibitors, including toripalimab, sintilimab, camrelizumab and tislelizumab (41). All the listed drugs in China have their own limited indications, and their effectiveness and safety in HCC is still under investigation in clinical trials (Table IV).

PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory genes, including CD274, CD8A, LAG3 and STAT1, have been developed with improved survival and response (47). Biomarkers have been reported to be associated with clinical outcomes (48). High PD-1 expression may indicate that T cells have been depleted in the tumor microenvironment (TME), which can help identify which type of patient will benefit from ICI therapy by inhibiting the PD-1/PD-L1 signal axis (39). Markers of systemic inflammation, such as elevated neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and α-fetoprotein are associated with poor prognosis in HCC (40).

Recent evidence suggest that when cells gradually evolve into malignant tumors, PD-L1 expression increases and the interaction between PD-1 and PD-L1 inhibits the self-reactive T cells, resulting in the over balance of PD-L1, PD-L2 and PD-1 (49). It has been demonstrated that androgen (AR) receptor can inhibit PD-L1 expression in HCC cells, and AR transcriptionally represses PD-L1 by binding to its promoter. In human clinical HCC samples, AR is negatively associated with PD-L1 expression (50). Thus, overexpression of AR weakens the effect of PD-L1 inhibitors in vivo.

Previous studies have demonstrated that EGFR signaling also regulates host antitumor immunity, including driving PD-L1 expression (51–53). In non-small cell lung cancer (NSCLC), the role of EGFR signaling on PD-L1 has made a breakthrough. Compared with NSCLC cell lines with wild-type EGFR, PD-L1 expression is significantly higher in cell lines with mutant EGFR (54). Using EGFR-TKIs (gefitinib or erlotinib) to inhibit EGFR can decrease PD-L1 expression in NSCLC cell lines with mutant EGFR (55). Increasing evidence suggest that inhibiting EGFR can modulate the TME, which will optimize the antitumor activity of immunotherapy and increase the number of patients who benefit from PD-1/PD-L1 inhibitors (51–55).

Nivolumab and pembrolizaumab have been brought into guidelines due to their exact efficacy (11). PD-1 and PD-L1 expression, biomarkers of inflammation, inflammatory genes, AR and EGFR signaling have clear evidence of the impact on PD-1/PD-L1 clinical outcomes (47–55). The reason why cemiplimab, atezolizumab, avelumab, durvalumab have not been included in the guidelines for the treatment of HCC is that their efficacy and safety is not completely certain, and several trials are still ongoing (29–40). Nivolumab as a first-line treatment option compared with sorafenib is still under research, and nivolumab may become first-line treatment if the result is positive (12–23); atezo+bev has potential as a first-line treatment for unresectable HCC; both avelumab and axitinib are known to be safe when administered as monotherapy; cemiplimab and durvalumab have also demonstrated effectiveness in ORR (30,33,35,37,40). With an increase in the number of clinical trails, cemiplimab, atezolizumab, avelumab and durvalumab may be added to the guidelines. The breakthrough of the IMbrave150 trial offers the best pick-me-up to the development and application of PD-1/PD-L1 inhibitors (31).

Recent Chinese effort on PD-1 and PD-L1 blockers has proved useful, including toripalimab, sintilimab, camrelizumab and tislelizumab (42–45). They are listed in China with their specific indications, and their efficacy and safety in patients with HCC is under research. The results have demonstrated that the combination of camrelizumab with FOLFOX4 or GEMOX chemotherapy is well tolerated, and this combination is expected to be effective for advanced HCC (43,44). In addition, tislelizumab has exhibited effectiveness in ORR (45). In each willingness to pay (WTP) threshold among different countries, United States has a high WTP, which is 10,000~150,000/quality- adjusted life year, while the PD-1/PD-L1 inhibitors produced by China are more cost-effective (56).

The present review introduces eight drugs targeting PD-1 and PD-L1 developed in the United States, France, England and China, two of which (nivolumab and pembrolizaumab) have been recommended as second-line options for patients with HCC by the NCCN clinical practice guidelines. ICIs targeting PD-1/PD-L1 have notably improved the symptoms of several patients with different malignant tumors. However, treatment is associated with typically transient immune-related adverse events (irAEs), which are severe or even deadly (57–59). Rapidly detecting these side effects and efficiently activating systemic immunosuppression can improve outcomes, without affecting the efficacy of ICIs (57). A common and early irAE associated with ICIs is dermatologic toxicity, which can lead to dermatologic/mucosal toxicity, and oral mucositis and/or dry mouth symptoms have been observed following treatment with PD-1/PD-L1 (58). Other common irAEs include diarrhea and effects on the adrenal, pituitary and thyroid glands, which are difficult to identify due to the atypical symptoms, including fatigue, headache and nausea. Less frequent irAEs are observed in the lung, eye, kidney and pancreas (59). Meta-analyses of treatment-related adverse events in 2018 and 2019 (60,61) demonstrated that the most common all-grade adverse events were fatigue, diarrhea and pruritus. The most common grade 3 or higher adverse events were anemia, fatigue and increased aspartate aminotransferase. Hypothyroidism (6.07%) and hyperthyroidism (2.82%) were the most frequent all-grade endocrine irAEs. In addition, the rates of hypothyroidism pneumonitis, colitis and hypophysitis were higher in the presence of anti-PD-1 drugs compared with standard treatment. Among the general adverse events associated with immune activation, only the incidence of rash increased, whereas the incidence of diarrhea and fatigue were similar to the control group (60,61).

With the rapid development of molecular immunology and molecular biology, immunotherapy has emerged as a novel strategy with some promising results. However, it is not without limitations. The influencing factors, such as AR, require further investigation to improve the clinical outcomes, along with the suitable combination therapy for elevating response rate. In addition, more biomarkers are required to accurately predict efficacy, and it is essential to overcome immunotherapy resistance.

Pharmacists can easily collect PD-1/PD-L1-related data to provide a reference for clinicians, and the available data indicates that the development of PD-1/PD-L1 inhibitors to treat HCC will provide more options for combination therapy, and improve outcomes in patients who do not respond to first-line treatment. Publication of the results of ongoing clinical trials of PD-1/PD-L1 inhibitors is believed to provide more data and insight for the effective treatment of HCC.