Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer worldwide, and due to its constantly increasing incidence, it has become the third leading cause of cancer-related death among general populations. Moreover, it represents the most common cause of death in patients with cirrhosis ^[1][2][1,2]. Multiple classification schemes are available to stratify HCC patients in an effort to determine which therapies they can undergo to increase their overall survival. The Barcelona Clinic Liver Cancer Staging (BCLC) system is one of the most widely used, and takes into account hepatic function, the extent of tumor involvement, and performance status [3].

The definitive therapies for HCC remain surgical resection and liver transplantation that can be performed only in patients at very early (0) and early (A) stages. However, given the similar survival benefit paired with the less invasiveness and lower costs compared to surgical resection, percutaneous ablative therapies such as radiofrequency ablation (RFA) and microwave ablation (MWA) are now considered the first treatment approach in both very early and early stages, especially in patients with small HCC (≤3 cm) ^[4][5][4,5]. Despite inducing an effective local antitumor effect, the responses to ablation techniques are relatively weak and might not completely control the tumor, as testified to by the high local recurrence rates. In particular, the size, number and location of tumors can be responsible for incomplete treatment response [6]; in addition, by promoting angiogenesis of residual cancer cells through both transcriptional and epigenetic regulations, insufficient ablation could lead to the recurrence of HCC with a more aggressive phenotype [7]. Therefore, novel techniques to improve ablation efficacy are currently being investigated.

Despite the improvement in screening and surveillance programs, most patients with HCC (about 65–70%) are still diagnosed in the intermediate (B) or advanced (C) tumoral stages, and are thus ineligible for radical therapies ^[8][9][10][8,9,10]; therefore, patients with intermediate and/or advanced HCCs are considered for transarterial therapies or systemic therapies ^[11][12][11,12] which, albeit effective, are deemed non-curative or “palliative” and still yield a lower 5-year survival rate ^[13][14][13,14]. According to BCLC tumor staging and management [3], transarterial chemoembolization (TACE) is recommended as first-line therapy for unresectable intermediate-stage HCC (stage B). Therefore, it is not surprising that this treatment was the most widely used first line treatment for the treatment of HCC across the world. More interestingly, instead, TACE emerged as the most frequently used first-line treatment for early and advanced stages, thus making it the most frequent treatment for HCC overall [8]. In fact, TACE is potentially suitable and safe for selected patients in the advanced stage with tumor vein thrombosis ^[15][16][17][15,16,17], or in combination with systemic therapies, without safety concerns ^[18][19][18,19]. Additionally, TACE can be safely and effectively performed in patients at very early and early stages that are partial responders to surgery or ablation, or that are unfit for these curative therapies due to contraindications [20], or prior to liver transplantation to downstage the tumor burden [21]. Despite evidence of beneficial short-term outcomes with locoregional treatments, recurrence and distant metastasis continue to have a significant effect on the overall survival of patients with HCC, especially in intermediate and advanced stages. This may be partly explained by the hypoxic environment created by the TACE procedure, which can induce neoangiogenesis by stimulating vascular endothelial growth factor (VEGF) and other angiogenic pathways, promoting revascularisation and growth of residual viable tumors or even new lesions [22]. Moreover, when it comes to transarterial therapies, one important consideration is that the blockade of hepatic arteries, especially if repeated several times, can compromise liver function and lead to collateral vessel formation, thus limiting the ability to repeat embolization by conventional hepatic vasculature ^[23][24][23,24]. In an effort to address this problem, many studies have been conducted combining TACE with systemic anti-angiogenic agents, most commonly sorafenib, with the aim to counteract this paradoxical effect and thus extend the clinical benefit derived from TACE. However, although most of these studies report the safety of the combination [18], a large number of clinical trials have failed to demonstrate any significant improvement in clinically relevant outcomes for patients with intermediate-stage HCC ^[25][26][25,26]. Even the more recent TACTICS trial, despite being the first study to demonstrate a longer progression-free survival (PFS) in patients receiving sorafenib plus TACE than in those receiving TACE plus placebo [27], it did not significantly extend overall survival (OS) in its final post-hoc analysis [28]. Therefore, better strategies to improve the outcomes for HCC patients treated with TACE are being developed.

Along with TACE, the role of other radiological locoregional therapies has expanded in recent years. For example, transarterial radioembolization (TARE) with yttrium-90 has been suggested as a safe and effective alternative treatment option for HCC patients with a liver-dominant disease who cannot tolerate systemic therapies ^[29][30][31][29,30,31], even with a significant cost advantage [32]. Moreover, the recent availability of new microspheres with a different radioisotope (such as 166-holmium) and the new technological developments will probably contribute to further reinforce the role of this option in HCC treatment and expand its clinical indication even in early and intermediate stages ^[33][34][33,34]. Nonetheless, due to the current lack of evidence demonstrating its superiority and non-inferiority to sorafenib, TARE is now recommended only in single HCCs ≤ 8 cm ^[3][35][3,35], and its role behind this indication remains uncertain.

Therefore, despite current limitations, the role of interventional radiology in the treatment of HCC is continuing to grow at each stage of the disease, especially at centers of excellence with multidisciplinary tumor boards, whether it is performed with curative, downstaging, bridging, debulking or palliative intent (Figure 1) ^[36][37][36,37]. Moreover, its expansion is expected to further progress as technical and clinical innovation continue to outpace large randomized controlled trials, with 50–60% of HCC patients that are expected to receive these treatments in their lifespan, globally [38].

In recent years, immunotherapy has led to a major shift in the treatment of HCC and prompted clinical trials, with therapeutic agents being used to selectively target immune cells rather than cancer cells [39]. In particular, the combination of atezolizumab and bevacizumab is now regarded as the standard first-line treatment for patients with advanced HCC due to the significant and clinically meaningful improvements in terms of OS, PFS, objective response rate (ORR) and complete response rate (CRR) compared with sorafenib monotherapy ^[3][40][41][3,40,41]. More recently, the combination of tremelimumab and durvalumab has been reported to be superior to sorafenib in patients with advanced or unresectable HCC, adding another first-line treatment option [42]. The impressive benefit provided by immunotherapy in patients with advanced HCC has led to the question if there is a rationale to support the combination of these new drugs with locoregional therapies in an adjuvant or neoadjuvant setting even in the early and/or intermediate stages [43]. In fact, it has now been demonstrated that locoregional treatments can positively alter the immune microenvironment of HCC and, theoretically, have a synergistic effect, further enhancing antitumor immune responses and thus improving patient survival [44].

2. The Immunogenic Proprieties of Hepatocellular Carcinoma

HCC arises almost exclusively in the setting of chronic liver diseases, and chronic inflammation is now regarded as one of the main triggers of hepatocarcinogenesis ^[45][46][47][45,46,47]. Since the background of chronic inflammation promotes immune suppression, there is a tightly interwoven, exceedingly complex relationship between HCC and the anti-tumor immune response in the liver. Due to the presence of an immune-suppressed microenvironment, HCC is indeed considered an immunogenic tumor [48]. First of all, chronic inflammation plays a key role in the initiation, evolution, and progression of neoplasms by creating a microenvironment that supports the malignant transformation of hepatocytes through hepatocellular DNA damage and genetic and epigenetic aberrations [49]. When liver damage occurs, thanks to the liver’s unique considerable ability to repair itself, differentiated hepatocytes can re-enter the cell cycle and serve as their own main source of replacement [50]. However, the chronic activation of non-parenchymal cells induces altered survival and proliferation signals, resulting in cellular stress, epigenetic modifications, mitochondrial alterations, DNA damage, senescence, and chromosomal aberrations. This leads to continual cell death, compensatory regeneration and liver fibrosis, which collectively induce tumorigenesis [51]. Moreover, the increased production of pro-inflammatory cytokines occurring in the setting of chronic inflammation promotes the expression of pro-oncogenic transcription factors (such as STAT3 and NF-κB), further contributing to HCC development [52]. Secondly, chronic inflammation can boost tumor immunogenicity, creating an immunosuppressive surrounding and allowing cancer cells to escape the host immune surveillance and progress [53]. One of the main functions of the liver is to continuously remove a large and diverse spectrum of pathogen components [i.e., pathogen-associated molecular patterns (PAMP)] and endogen molecules derived from damaged or necrotized cells [i.e., damage-associated molecular patterns (DAMPs)] from the circulation, thus ensuring organ protection by maintaining immunotolerance [54]. In chronic liver diseases, however, this tightly controlled immunological network is deregulated, thus leading to the failure of efficient detection and the elimination of transformed cells and causing the breakdown of proper tolerance [53]. Once HCC has developed, an intra-tumor infiltration by lymphocytes occurs, in an attempt by the host to mediate an anti-tumor reaction [55]. Under normal circumstances, tumor antigens would be internalized by the host antigen-presenting cells (APCs) and then, after being processed, be bonded to Major Histocompatibility Complex II (MHC-II) molecules. Subsequently, if properly stimulated, dendritic cells would present these tumor antigens to T cells located in the lymphatic organs, thus promoting their activation and the stimulation of effector cells, including CD8+ T cells and Natural Killer (NK) cells. Once activated, tumor-specific effector cells would migrate from lymph nodes to the tumor location, where they would exert their cytotoxic effect on neoplastic cells. Unfortunately, these cellular responses can be dysfunctional and unable to efficiently eliminate cancer cells, thus leading to HCC progression [56]. Tumoral cells can indeed promote an elevated production of immunosuppressor cytokines (such as IL-10 and TGFβ1) that downregulate the anti-tumor response at different levels. The number of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) increases in the HCC microenvironment, which directly inhibits the tumor killing effect of NK cells and CD8+ T cells through overexpression of multiple factors [57]. In addition, MCH II is often functionally depleted in HCC, thus being unable to induce the activation of CD8+ T cells and leading to tumor immune escape [58]. Furthermore, tumoral cells inhibit the activation of APCs and promote the M2 polarization of macrophages, thus further impairing the effector functions of CD8+ T cells and NK cells ^[59][60][59,60]. Lastly, there is an abnormal expression and function of immune checkpoint molecules that, rather than preventing the excessive immune response from injuring normal hepatocytes as it happens in normal conditions, inhibit the host immune function and thus promote the growth of tumor cells. In particular, the most studied of them are programmed cell death protein 1 (PD-1) and its ligand (PD-L1), which leads to the T-cell exhaustion status, and cytotoxic T-lymphocyte protein 4 (CTLA-4), which inhibits the activation of T cells ^[61][62][61,62]. The current combined strategy of immunotherapy and locoregional treatments essentially aims to enhance the effects of immune checkpoint inhibitors (ICIs) that selectively target these immune checkpoints (PD-1/PD-L1 and CTLA-4); therefore, rather than stimulating new or different immune responses, ICIs can restore and unleash a preexisting immune reactivity to cancer which is being held in check by tumoral microenvironmental factors (Figure 2) ^[63][64][63,64].