Image-guided locoregional therapies (LRTs) have the potential of shaping tumor immunity by altering the composition of the HCC microenvironment; in particular, they lead to the release from dying tumor cells of cryptic TAAs and tumor neoantigens that become accessible to the immune system, acting as novel targets for antigen-presenting cells (APCs), mainly dendritic cells (DCs).

The innate immune system, including neutrophils, macrophages, and natural killer (NK) cells, is the first to respond, followed by the more strong and sustained acquired response [33,34], characterized by significant intratumoral immune infiltrates [35,36,37,38,39,40]. In order to stimulate the acquired immune system, cancer cells must die thorough immunogenic cell death (ICD), which happens with necrosis and is characterized by the release from dying cells, along with antigens and preserved intracellular organelles, of damage-associated molecular patterns (DAMPs), such as DNA, RNA, heat shock proteins (HSPs), adenosine triphosphate (ATP), protein high-mobility group box 1 (HMGB1), calreticulin, and uric acid, which allow recruitment and activation of DCs (through the NF-κβ pathway activation). Activated DCs, after reaching regional lymph nodes, present antigens along with costimulatory signals to T cells that are therefore stimulated [41,42,43]. On the contrary, in non-ICD, which occurs with apoptosis, the dying tumor cells do not release DAMPs; without phagocytizing DAMPs, DCs cannot be activated and therefore do not present costimulatory signals to T cells [43,44], with the subsequent T-cell anergy and deletion leading to immune tolerance [45,46,47]. The antitumor response triggered by ICD takes place both locally and distantly from the primary tumor; this phenomenon, whereby a locally applied therapy elicits a distant antitumor response, is known as the abscopal effect [48].

It is not yet clear which ablative technique has the highest potential for releasing cryptic tumor antigens and creating the best immunostimulatory microenvironment.

All locoregional and surgical approaches might also have a stimulatory effect of oncogenesis, as described by several studies, by means of tumor cell spreading, microenvironmental changes, and both angiogenetic and proliferative triggers.

In fact, LRTs, both thermal and non-thermal, applied to the liver as well as to other organs, have been correlated to a more aggressive tumor subtype, tumor growth [49,50,51], and to a higher incidence of tumor progression [52,53]. This can be attributed to local and systemic inflammation (via an increase in IL-6, IL-8, and HSP) and to the upregulation of pro-oncogenic growth factors such as hypoxia-inducible factor-1α (HIF-1α), VEGF, hepatocyte growth factor (HGF), hepatocyte growth factor receptor (HGF-R), matrix metalloproteinases (MMPs), cluster of differentiation 147 (CD147), and mammalian target of rapamycin (mTOR) [49,54,55,56,57,58,59,60]. Moreover, local hepatic thermal ablation has been linked, in some cases, to a higher rate of distant intrahepatic tumor development and to overall worse outcomes [50,53,60,61]. This may be particularly true for sublethal–incomplete treatments [62,63,64].

3. LRTs: Classification