Surgical resection is the recommended course of treatment for localized ccRCC (7). The commonly used nephrectomy modalities are radical nephrectomy (RN) and nephron-sparing surgery (NSS). RN means removing the entire kidney, perinephric adipose tissue (PAT), and Gerota’s fascia, where the lesion locates. It was once thought to be the only cure for localized renal cancer. However, RN leads to acute loss of nephron, sharply increases the load of the contralateral kidney, and can easily trigger acute postoperative kidney injury (8). NSS only removes part of the diseased kidney tissue, preserving as much of the ipsilateral normal kidney unit as possible. Nevertheless, NSS is a long procedure and is prone to common complications such as hematuria, perirenal hematoma, and urinary fistula (3, 9). As long as it is technically feasible, the guidelines recommend prioritizing NSS for patients with T1 and T2 (10).

The treatment modality to remove the primary tumor despite the metastasis has already occurred is known as CN (11). CN has long been considered as the standard of care for most patients with mccRCC. However, a recent clinical trial stated that sunitinib combined with CN was not superior to sunitinib alone and questioned CN as a form of overtreatment (12). Conversely, another study reported that the implementation of CN is beneficial for the survival of some patients with a giant primary tumor, fewer metastatic lesions, and better physical condition (12, 13). CN plays a synergistic role in immunotherapy by erasing the primary tumor and thus removing cytokines and proteins that inhibit the immune response (14). The controversial issue of CN prompts us that with advancing and evolving in medical techniques, the necessity of conventional surgical treatment for mccRCC patients should be evaluated properly. Rather than blindly denying the role of CN, we should accurately define the patients who can benefit from CN and recommend time of surgery for them through scientific means such as risk scoring (15).

Surgical procedures are less suitable for elderly patients with poor physical status, patients with bilateral tumors in the kidneys, and patients with only a single kidney remaining (16). The advent of tumor ablation has brought an effective alternative for such patients. Tumor ablation is a local tumor control method, which ablates the tumor and healthy tissues beside the tumor by placing a probe in the central area of the tumor under the guidance of imaging (17). Compared with traditional surgery, tumor ablation has the advantages of being minimally invasive, having a short treatment time, and being able to carry out repeatedly. Currently, the commonly used clinical ablation techniques are radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation (CA) (18). RFA and MWA are thermal ablations that use high temperatures to cause coagulation necrosis of cells (19). CA uses argon to cool the probe to −160 °C and below rapidly, then helium to slowly re-warm the target tumor to 20-40 °C, and the cooling and re-warming cycles repeat (16). This cold-hot alternating freeze-thaw cycle can trigger cellular damage, vascular damage, apoptosis, and immune effects in tumors (16, 20). Compared to thermal ablation, CA is less unpleasant, has distinct ablation boundaries, and is safer (21). However, the cooling capacity of CA is positively correlated with the diameter of the probe, which limits its ablative capacity (16). Moreover, CA is expensive and time-consuming compared to thermal ablation. Available studies have shown that for tumors ≤4 cm in diameter, the effectiveness of MWA and RFA treatment is indistinguishable, and thermal ablation is slightly more effective than CA (22, 23).

For individuals with metastases, systemic therapy is not always necessary, but should be considered. Chemotherapy is one of the most well-known systemic treatments, but mccRCC is not sensitive to chemotherapy. The spontaneous tumor regression in a minimal number of mccRCC patients has focused attention on the anti-tumor response of the immune system. Cytokines, soluble proteins released by cells with the ability to modulate the immune system, were the first anti-cancer immune substances to receive attention, ushering in the era of prior immunotherapy (24). Studies have shown that the median overall survival (OS) of low-, intermediate-, and high-risk patients who received cytokine therapy was 27, 12, and 6 months, while the median OS of these three categories of patients who received chemotherapy was 15, 7, and 3 months, respectively (25). This suggests that cytokine therapy is slightly superior to chemotherapy in the treatment of mccRCC.

Interferon (IFN)-α (particularly IFN-α 2a) and interleukin (IL)-2 are cytokines routinely utilized clinically for the treatment of mccRCC. IFN-α is the largest isoform of interferon, with a broad spectrum of antiviral and immunomodulatory effects. Around 1972, IFN-α began to be employed in anticancer therapy (26). An early prospective randomized trial found that the total effective rate of IFN-α coupled with vincristine was 16.5%, higher than 2.5% of vincristine alone. And the median survival duration of patients who underwent combination therapy was 67.6 weeks, but that of patients who only received vincristine chemotherapy was 37.8 weeks (27). In 1994, IL-2 was approved for the treatment of mccRCC. In 1998, it was approved to treat metastatic melanoma (28). IL-2 has numerous biological functions, including activation of T cells, induction of cytotoxicity, boosting B cell proliferation, and secretion of antibodies, and other (29). All these evidences demonstrate that direct administration of exogenous cytokines can impact the development of tumors and modulation of the immune system is an effective cancer treatment.

Compared to chemotherapy, cytokine therapy does improve the responsiveness of patients with mccRCC. However, this therapy is associated with numerous adverse effects that severely affect the quality of patients’ survival. Adverse effects of IFN-α therapy include loss of appetite, fatigue, nausea, malaise, chills, and dry mouth (30, 31). Conventional doses of IL-2 have limited efficacy. Although higher doses increase the therapeutic capacity of IL-2, they can lead to adverse effects such as vascular leakage syndrome and other cytokine storms (32–34). Observational data on the efficacy of a group of patients treated with high doses of IL-2 for mccRCC showed that roughly 4% of patients died from adverse events related to IL-2 therapy (35). Numerous adverse events and low targeting are bottlenecks that are difficult to break through in cytokine therapy and are the main reasons for the gradual withdrawal of cytokines from the first-line medication ladder.

Notably, the cytokine era has developed a commonly used prognostic risk model for advanced/metastatic RCC, the Memorial Sloan Kettering Cancer Center (MSKCC) score. The score includes five risk factors, namely ① time from diagnosis to systemic therapy, ② physical status, ③ blood calcium, ④ hemoglobin, and ⑤ lactate dehydrogenase. According to the number of risk factors, patients could be divided into three groups: low, medium, and high risk, corresponding to a median OS of 30, 14, and 5 months, respectively ( Table 2 ).

From about 2000 to 2010, targeting the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR) signaling pathway was the standard treatment to ccRCC (36). Von Hippel-Lindau (VHL) is the tumor suppressor of ccRCC and its inactivation blocks the degradation pathway of hypoxia inducible factor α (HIFα) (37). Highly expressed HIFα upregulates VEGF, thus promoting increased vascular permeability and angiogenesis, stimulating endothelial cell proliferation and migration, protecting endothelial cells from apoptosis, and promoting tumor invasion (38). Therefore, anti-angiogenesis has been used as a policy in targeting therapy. Currently, approaches to inhibit the VEGF pathway are broadly divided into two categories. The first type of strategy is to block the VEGF receptor (VEGFR) to block binding of VEGF to endothelial cells. The second type of strategy is to prevent the activation of VEGFR by human-derived monoclonal antibodies binding to circulating VEGF (39).

Tyrosine kinase inhibitor (TKI) is a multi-target receptor inhibitor. In ccRCC, TKI mainly inhibits VEGF signaling by targeting VEGFR-2 inhibition (38). TKI for mccRCC include sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib, and tivozanib (40). Among them, the oral angiogenesis inhibitors sunitinib, pazopanib and cabozantinib are the first-line treatment options.

Sorafenib was the first TKI marketed for mccRCC. In phase II clinical study, sorafenib was not superior to IFN-α’s ability to prolong median progression-free survival (PFS). However, in terms of the proportion of patients with reduced tumor volume, sorafenib was higher than IFN-α (68.2% vs. 39.0%) (41). A 2007 clinical trial showed that objective response rate (ORR) in sunitinib-treated group was 31%, with a median PFS of 11 months, while the ORR was only 6% and a median PFS was 5 months in IFN-α-treated group (42). This trial demonstrated firstly that sunitinib was superior to IFN-α in treating mccRCC and led to replacement of cytokines by targeted drugs as the standard of care for mccRCC. Pazopanib was non-inferior to sunitinib to prolong PFS but had a better safety profile than sunitinib. For previously untreated patients, the pazopanib-treated group had an ORR of 30% and a median PFS of 11.1 months (43). Moreover, the incidence of adverse events such as hand-foot syndrome due to pazopanib treatment is lower than that of sunitinib (44). Axitinib inhibits intracellular VEGFR autophosphorylation with picomolar half maximal inhibitory concentration (IC₅₀) values (45). Its IC₅₀ for VEGFR1, VEGFR2, and VEGFR3 was significantly lower than sorafenib, sunitinib, or pazopanib. A randomized phase III trial divided 723 patients with advanced RCC into two groups. One group was treated with axitinib (5 mg twice daily), and one group received sorafenib (400 mg twice daily). The median OS in the axitinib-treated group was 20.1 months, the median PFS was 8.3 months, while the median OS in the sorafenib-treated group was 19.2 months, and the median PFS was 5.7 months (46, 47). The ability of axitinib to prolong OS was not significantly different from sorafenib. Nevertheless, its ability to prolong PFS was superior to sorafenib. This result establishes axitinib as a second-line treatment for mccRCC. Cabozantinib is an oral small molecule TKI that inhibits tumor vascular regeneration by inhibiting signaling pathways such as VEGFR and hepatocyte growth factor. A phase I trial used it to treat 25 patients with RCC who had failed standard therapy. Cabozantinib demonstrated preliminary antitumor activity and safety, with a median PFS of 12.9 months and a median OS of 15.0 months (48). Lenvatinib is a dual inhibitor of VEGFR and fibroblast growth factor receptor, which is generally used in combination with other drugs to treat RCC. The TIVO-3 trial compared tivozanib (1.5 mg once daily) with sorafenib (400 mg twice daily) in advanced RCC. The results showed that tivozanib did not differ from sorafenib’s ability to prolong OS. It was better than sorafenib in prolonging PFS (5.6 months vs. 3.9 months) as a third- or fourth-line treatment for mccRCC (49, 50).

Bevacizumab is the first recombinant humanized monoclonal antibody against VEGF. Patients have a median PFS of 10.2 months in the group treated with combination of bevacizumab and IFN-α, compared with 5.4 months in the group treated with placebo plus IFN-α (51, 52). Because bevacizumab, combined with IFN-α, significantly improved PFS in patients with mccRCC, it was approved by European Medicines Agency and US Food and Drug Administration (FDA) as a first-line agent for the treatment of advanced mccRCC around 2007. A phase III trial in 2022 showed that bevacizumab in combination with atezolizumab (an ICI) was not superior to sunitinib alone for the treatment of mccRCC (53). Currently, bevacizumab is not used in the treatment anymore.

mTOR inhibitors, which also inhibit angiogenesis, are an option for patients with advanced kidney cancer who are drug-resistant or failed to VEGF-targeted therapy. In ccRCC, the mTOR signaling pathway is hyperactivated to inhibit apoptosis and promote cancer cell proliferation and neovascularization (54). Compared to VEGF inhibitors, mTOR inhibitors are more potent in inhibiting cell proliferation and less potent in inhibiting neovascularization (55). In mccRCC, the commonly used mTOR inhibitors are temsirolimus and everolimus, both target mTOR complex 1 (56, 57). In a multicenter, phase 3 trial, 626 previously untreated patients were randomly assigned to the IFN-α treatment group, the temsirolimus treatment group, and the temsirolimus combined with IFN- α treatment group. The median PFS of patients in the three treatment groups were 3.1, 5.5, and 4.7 months, respectively. The median OS was 7.3, 10.9, and 8.4 months, respectively (58). Temsirolimus improved OS and PFS in patients with mccRCC compared to IFN-α, although the combination of temsirolimus with IFN-α was not superior to temsirolimus monotherapy. Unlike temsirolimus, administered intravenously, everolimus is an oral mTOR inhibitor. A randomized, double-blind phase 3 trial divided patients with mccRCC who received TKI therapy into two groups in a 2∶1 ratio: everolimus-treated and placebo groups. The median PFS in the two groups was 4.0 months and 1.9 months, respectively (59). Thus, everolimus became a recommended drug in clinical practice guidelines after the failure of first line VEGFR-TKI therapy (55).

Notably, the combination of lenvatinib with everolimus significantly improved patients’ median PFS (14.6 months vs. 5.5 months) and median OS (25.5 months vs. 15.4 months) compared to everolimus monotherapy. This combination regimen has been used in the second-line treatment of advanced RCC (60, 61). Similarly, a phase III trial compared cabozantinib with everolimus to treat advanced RCC. The trial divided 658 patients equally into a cabozantinib-treated group (60 mg once daily) and an everolimus-treated group (60 mg once daily). Cabozantinib showed an advantage in PFS (7.4 months vs. 3.8 months) and ORR (17% vs. 3%) compared to everolimus. Based on this, FDA approved cabozantinib for second-line treatment of metastatic RCC in 2016 (62). The Alliance A031203 CABOSUN trial divided 157 patients with metastatic RCC into a cabozantinib treatment arm (60 mg once daily), a sunitinib treatment arm (50 mg once daily; 4 weeks on, 2 weeks off). Cabozantinib had an even better ability to prolong median PFS (8.2 months vs. 5.6 months) and improve ORR (33% vs. 12%) compared to the standard first-line drug sunitinib (63, 64). Following the completion of the Phase II CABOSUN trial, FDA subsequently approved cabozantinib as first- and second-line therapy for mccRCC.

Although VEGF inhibitors and mTOR inhibitors can significantly improve disease control rates and prolong patient survival in ccRCC, they still cause a few adverse effects. TKI therapy frequently results in negative side effects such as hypertension, hand-foot syndrome, vomiting, and diarrhea (42). Adverse effects of bevacizumab are mainly manifested by its toxic effects on the gastrointestinal, cardiovascular, hematological, and urinary systems (65). Everolimus has fewer severe side effects, including common stomatitis, rash, and diarrhea (59). However, drug resistance and hyposensitivity are currently the most critical issues to be tackled with targeted therapies, not adverse events. Drug resistance in targeted drug therapy typically arises 6 to 11 months after treatment initiation and is caused by compensatory vascular proliferation due to hypoxic response (54, 66, 67). Tumor heterogeneity, the cause of hyposensitivity, is a huge problem to be conquered in the overall field of oncology treatment.

For the prognostic model of RCC, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria were established in the era of targeted therapy based on the MSKCC criteria. IMDC criteria include neutrophil and platelet levels as risk factors and exclude lactate dehydrogenase. Patients could be classified into three groups according to the risk factors: low, intermediate, and high risk, corresponding to a median OS of 35.3, 16.6, and 5.4 months, respectively ( Table 2 ).

ICI therapy is a new generation of immunotherapy designed to restore or improve the efficiency of the body’s immune system against tumors by abolishing the immune escape mechanism of tumors with ICI. Immune checkpoints are “brake pads” that negatively regulate T-cell function to avoid overactivation of the immune system. Programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) are all currently identified immune checkpoints (68). PD-1 and CTLA-4 are immune test sites distributed on the surface of T cells, and PD-L1 is the ligand for PD-1 that is highly expressed in tumor cells. Tumor cells could turn off the ability of T cells to kill tumor cells by overexpressing PD-L1. Cluster of differentiation (CD) 80 and CD86 expressed on antigen-presenting cells (APC) can bind to CTLA-4 on T cells and deliver signals that suppress immune responses. ICIs restore the aggressiveness of the immune system against tumor cells by blocking the binding process of the receptors mentioned above to ligands mentioned above. Nivolumab, pembrolizumab, atezolizumab, avelumab and ipilimumab are common ICIs used to treat mccRCC.

Nivolumab is a PD-1 inhibitor, and CheckMate-025 compared its efficacy with everolimus in advanced RCC (69). Subjects were patients who had previously received one or two kinds of anti-angiogenic therapies. Patients in the nivolumab-treated group had a median OS of 25 months, an ORR of 25%, and a median PFS of 4.6 months. Patients in the everolimus-treated group had a median OS of 19.6 months, an ORR of 5%, and a median PFS of 4.4 months. Although there was no significant difference in median PFS between the two groups, the ability of nivolumab to prolong OS and improve ORR was superior to everolimus. Pembrolizumab is also a common PD-1 inhibitor. In a single-arm phase II study, patients with advanced ccRCC were given 200 mg of pembrolizumab intravenously every three weeks. The ORR was 36.4%, and the disease control rate was 58.2% (70). A double-blind, phase 3 trial divided patients who had undergone nephrectomy into two groups. With 496 patients treated with pembrolizumab and 498 patients treated with placebo (71). Disease-free survival was significantly longer in the pembrolizumab-treated group compared to the placebo (disease-free survival at 24 months, 77.3% vs. 68.1%). It shows that pembrolizumab alone has shown excellent antitumor activity. Atezolizumab is a monoclonal antibody targeting the PD-L1 protein. A 2019 clinical trial assigned 915 previously untreated mccRCC patients to two groups: the atezolizumab combined with bevacizumab treatment group and the sunitinib treatment group. Treatment results showed that the median PFS of patients in the combined treatment group was 11.2 months and that in the sunitinib group was 7.7 months (72). Compared to sunitinib, the combination therapy prolonged PFS and showed a good safety profile but failed to gain OS benefit. Therefore, the combo atezolizumab-bevacizumab cannot be considered standard treatment compared to other with OS improvement. Avelumab is a PD-L1 antibody that can be used with axitinib to treat advanced RCC. In a phase III JAVELIN Renal 101 trial, 442 patients received the avelumab (10 mg/kg once every two weeks)-axitinib (5 mg twice daily) combination. Another 444 patients received sunitinib (50 mg once daily for the first 4 weeks of each 6-week cycle). Among the 560 PD-L1-positive patients, the median PFS (13.8 months vs. 7.2 months) and ORR (55.2% vs. 25.5%) were significantly higher in the combination treatment group than in the sunitinib treatment group (73). Ipilimumab, a monoclonal antibody to CTLA-4, was the first ICI approved for clinical use, initially for the treatment of metastatic melanoma (68). CheckMate-214 showed an ORR of 42% and a median PFS of 11.6 months in patients with advanced ccRCC treated with the combination of nivolumab and ipilimumab, significantly better than the 27% and 8.4 months, respectively, in the sunitinib-treated group (74). Moreover, the extended follow-up of this clinical trial showed that the combination therapy maintained a significant OS benefit compared to sunitinib (75). The superior OS and ORR make this immunotherapy combination a new standard of care option.

It is not difficult to discover that ICI therapy is always used in conjunction with other treatments to combat drug resistance. The pairwise or multiple combinations of the above-mentioned classical clinical treatments has become a research hotspot in the ccRCC area. For example, stereotactic ablative body radiotherapy (SABR) combined with ICI therapy, TKI and ICI therapy combined, the combination of two kinds of ICI therapy, and so on (75–77).

The RAPPORT trial evaluated the safety and efficacy of a short course of anti-PD-1 immunotherapy after SABR in patients with mccRCC. A single fraction of SABR to all metastatic sites followed by 200 mg pembrolizumab administered Q3W for eight cycles. The results showed excellent local control with an ORR of 63% and disease control of 83% (76). In the combination of TKI and ICI, the combos axitinib-pembrolizumab, lenvatinib-pembrolizumab, and cabozantinib-nivolumab are the standard of care for first-line setting. In a phase III trial, 861 patients were divided into axitinib (5 mg twice daily)-pembrolizumab (200 mg by IV every 3 weeks) treatment group or sunitinib treatment group (50 mg once daily for the first 4 weeks of each 6-week cycle). The median PFS of 15.1 months and ORR of 59.3% were significantly better in the combination treatment group than in the sunitinib treatment group at 11.1 months and 35.7% (78). In another phase III trial, 1069 patients with advanced RCC who had not received prior systemic therapy were randomized equally into three groups: the lenvatinib (20 mg once daily)-pembrolizumab (200 mg by IV every 3 weeks) treatment group, the lenvatinib (18 mg once daily)-everolimus (5 mg once daily) treatment group, or the sunitinib (50 mg once daily for the first 4 weeks of each 6-week cycle) treatment group. The median PFS in the three groups was 23.9 months, 14.7 months, and 9.2 months, respectively. Moreover, the OS was longer in the lenvatinib-pembrolizumab group than in the sunitinib group but not in the lenvatinib-everolimus group (79). This trial establishes lenvatinib-pembrolizumab as a first-line treatment. In addition, another trial investigated the efficacy and safety of cabozantinib (40 mg once daily)-nivolumab (240 mg every 2 weeks) compared to sunitinib (50 mg once daily for the first 4 weeks of each 6-week cycle) in advanced RCC. The one-year OS probability was 85.7%, and ORR was 55.7% in the cabozantinib-nivolumab treatment group, higher than the 75.6% and 27.1% in the sunitinib treatment group, respectively (80). A long-term follow-up showed a median OS of 37.7 months in the combination therapy group, slightly better than 34.3 months in the sunitinib group. Not only that, the ability of combination therapy to prolong median PFS was significantly better than sunitinib (16.6 months vs. 8.3 months). This follow-up further supports cabozantinib-nivolumab in the first-line treatment of advanced RCC (81). Nivolumab plus ipilimumab is a typical combination of two ICIs for treating advanced RCC. The CheckMate 214 trial divided the 1096 intent-to-treat population into a nivolumab-ipilimumab treatment arm or a sunitinib treatment arm. Extended follow-up showed that the combination therapy was superior to sunitinib in extending OS (median not reached vs. 37.9 months) and improving ORR (41% vs. 34%) in intent-to-treat patients (75).

While the survival rate of mccRCC patients is undoubtedly increased by the combination of classical clinical therapies, fully durable responses are rare currently (82). Additionally, combined therapies have limited effects on patients who are insensitive to anti-angiogenic therapies and have failed ICI treatment (83). Therefore, it is necessary to devote part of our efforts to the study of new therapeutic strategies.

Currently, three categories of emerging therapeutic strategies have entered clinical trials: ① new targeted drugs, ② HyperAcute Renal (HAR) immunotherapy, and ③ emerging drugs in combination with classic drugs ( Table 3 ).

HIF2α inhibitors are undoubtedly the most promising emerging targeted drugs in recent years. As shown in Figure 2 , the inactivation of VHL with blockage of the degradation pathway of HIFα is an essential molecular feature for the induction of ccRCC. VHL encodes pVHL, which connects with ElonginB and ElonginC through a short collinear region to form the VCB structure. VCB structure interacts with the amino-terminal of CUL2. At the same time, the carboxyl-terminal of CUL2 interacts with RBX1 of the Ring E3s to form a VBC (VHL-ElonginB/C-CUL2) complex (84). VBC complex is a common E3 ubiquitin ligase enzyme. The pVHL serves as the substrate recognition subunit of this complex and is responsible for targeting HIFα for degradation via the ubiquitin-proteasome pathway (85). HIFα is a hypoxia-inducible factor that includes HIF1α and HIF2α. Under normal conditions, it maintains the stability of the internal environment in response to tissue hypoxia. In ccRCC, VHL alteration leads to the inactivation of pVHL, which results in the inhibition of HIFα degradation (37). At this point, even if external oxygen is sufficient, the uninhibited HIF α begins to exert its biological effects. It enhances tumor cells’ growth and their resistance to treatment by regulating the expression of VEGF, glucose transporter-1 (GLUT1), and other downstream target genes to improve tissues’ angiogenesis and glycolysis ability (84). As described in section 2.3, most currently available targeted drugs target the downstream target VEGF, but Petolon Therapeutics has successfully developed HIF2α inhibitors in recent years. A phase I dose-escalation trial used the first-generation HIF2α inhibitor MK-3795 (previously known as PT2385) to treat previously treated patients with advanced ccRCC. Results showed that MK-3795 was well tolerated, with complete remission, partial remission, and disease stabilization rates of 2%, 12%, and 52%, respectively (86). In a mouse xenograft tumor model, the second-generation HIF2α inhibitor MK-6482 (also known as belzutifan, formerly PT2977) was approximately ten times more potent than MK-3795. Subsequently, belzutifan, which is more selective and has better pharmacological properties, was also entered into a phase I clinical trial. Results showed an ORR of 25% and a median PFS of 14.5 months in ccRCC patients treated with 120 mg of belzutifan once daily (87). Belzutifan showed good tolerability and preliminary antitumor activity. In late 2021, a Phase II single-arm trial of belzutifan was completed. Patients with RCC receiving 120 mg of belzutifan once daily had an ORR of 49%. Belzutifan demonstrated activity in treating VHL disease associated RCC (88). Furthermore, to guarantee a new treatment option for patients in the shortest possible time, FDA has granted belzutifan breakthrough drug status (89).

In addition, triggering adenosine 2A receptors (A2AR) are highly expressed in RCC. Adenosine binding to A2AR would mediate immunosuppression in the tumor microenvironment. Ciforadenant is a small molecule inhibitor that targets A2AR and has acted in various preclinical tumor models. In a phase I trial using ciforadenant to treat refractory RCC, the blocker showed a favorable safety profile and preliminary efficacy (90). Kidney injury molecule 1, also known as T cell immunoglobulin mucin-1 (TIM-1), is predominantly expressed on many immune cells and tumor cells. CDX-014, an antibody-coupled drug targeting TIM-1, has shown a controlled toxicity profile and preliminary activity in a phase I trial to treat advanced RCC (91). Carbonic anhydrase IX (CAIX) is a downstream target protein inhibited by VHL. Due to VHL mutations, 95% of ccRCC cells show overexpression of CAIX. Girentuximab, a chimeric monoclonal antibody effectively targets CAIX, has been reported to have good tolerability and tumor uptake, with efficacy to be further determined in subsequent experiments (92).

HAR immunotherapy is an emerging immunotherapy evaluated in many tumors. In RCC treatment, HAR consists of two allogeneic kidney cancer cell lines genetically modified to express alpha-1,3-galactosyltransferase (α (1,3)Gal). Because humans are intrinsically immune to α (1,3)Gal, HAR immunotherapy immunizes patients against metastatic RCC cells using naturally occurring xenograft and zoonotic infection barriers. The therapy is well tolerated in the kidney and has the potential as a candidate for metastatic RCC (93).

Consistent with multiple classical drug combination therapies, the fervor of new drug-older drug combinations in clinical research cannot be underestimated. Bempegaldesleukin is a prodrug drug for IL-2, modified to provide low toxicity, controlled and sustained activation of the IL-2 pathway, and stimulation of antitumor immune responses. The PIVOT-02 study demonstrated encouraging clinical activity and tolerability of bempegaldesleukin combined with nivolumab, warranting further study (94). Telaglenastat, an oral glutaminase inhibitor, is a crucial enzyme that supports abnormal tumor metabolism. Sixty-nine patients in the ENTRATA trial were divided into two groups in a 2:1 ratio and treated with either telaglenastat- everolimus or placebo-everolimus. The results showed that telaglenastat-everolimus treatment was well tolerated and better prolonged PFS in patients with advanced RCC compared to placebo-everolimus treatment (3.8 months vs. 1.9 months) (95). Similarly, telaglenastat in combination with cabozantinib showed good tolerability and clinical activity (96). CBM588 is a bifidogenic live bacterial product with the potential to enhance ICI response by modulating intestinal flora. In a phase I trial, 30 patients with RCC who had failed previous treatment were divided into two groups. One group was treated with CBM588 - nivolumab - ipilimumab, and the other group was treated with nivolumab - ipilimumab. PFS was significantly longer in the three-drug treatment group than in the two-drug combination group (12.7 months vs. 2.5 months). The effect of CBM588 on ICI treatment warrants further study (97).