DCs act as the central link between innate defenses and adaptive responses. By capturing, processing, and presenting antigens, they prime naïve T cells and launch antitumor immunity. When DCs are dysfunctional, antigen display and immune priming decline, weakening clinical responses to immunotherapy (42).

Cirrhosis, a condition in which chronic inflammation, immune activation, and immune suppression coexist, markedly reshapes DC biology. Multiple clinical investigations describe lower peripheral DC counts together with altered subset balance. For example, Cardoso and colleagues reported that individuals with acute decompensated (AD) or stable cirrhosis (SC) had fewer total DCs, a higher plasmacytoid/classical DC (pDC/cDC) ratio, and elevated concentrations of interleukin (IL)-6 and IL-10 compared with healthy controls—findings consistent with simultaneous inflammation and suppression (18). In acute-on-chronic liver failure (ACLF), functional impairment is even greater. Wu et al. showed that monocyte-derived DCs (MoDCs) downregulate human leukocyte antigen (HLA)-DR, CD86, and CD54, display reduced antigen-presenting and T-cell-stimulating capacity, and produce inadequate levels of interferon (IFN)-γ (19). With advancing cirrhosis, maturation and priming functions become increasingly restricted. Notably, cultured MoDCs obtained from patients can reacquire mature phenotypes, characterized by expression of CD80, CD86, and HLA-DR, and effectively activate tumor antigen-specific T cells, indicating that their intrinsic antigen-presenting capacity is preserved (43).

Within the HCC microenvironment, cDCs are depleted and pDCs are functionally compromised. Upregulation of IL-10 and PD-L1 promotes tolerogenic DC states that dampen CD8⁺ T-cell activation and antitumor activity (20, 21, 44). The cirrhotic liver milieu, enriched in IL-10 and transforming growth factor (TGF)-β, further suppresses DC maturation and antigen presentation while expanding regulatory T cells (Tregs), thereby limiting effector responses (45). TGF-β can also drive immature DCs to generate antigen-specific CD8⁺ Tregs that inhibit other effector T cells and foster tumor tolerance (46).

However, research indicates that in CCL4-induced mouse models of liver fibrosis, fibrotic liver dendritic cells (FLDCs) exhibit a distinct and mature phenotype compared to normal liver dendritic cells (NLDCs). Expression of MHC II and CD40, the key molecules for antigen presentation, is upregulated in FLDCs. FLDCs exhibit significantly enhanced immunogenicity in both in vivo and in vitro experiments, which correlates with their secretion of TNF-α. FLDCs more effectively activate NK cells, inducing higher levels of IFN-γ production and increased cytotoxicity, while also enhancing the proliferation and activation of CD4⁺ and CD8⁺ T cells. Immunization with FLDCs completely prevents tumor development in mice (47). Jiao et al. demonstrated that following CCL4-induced liver fibrosis in mice, the number of hepatic cDCs and pDCs significantly increased during the early fibrotic regression phase after drug withdrawal, playing a crucial role in fibrosis reversal. Depletion of DCs in CD11c-DTR mice markedly delayed fibrosis regression and reduced clearance of activated hepatic stellate cells. Conversely, both Fms-like tyrosine kinase-3 ligand (Flt3L) expanded DCs and purified DCs accelerated fibrosis regression upon adoptive transfer. This effect primarily involved DC-secreted MMP-9 promoting extracellular matrix degradation (48).

Taken together, cirrhosis reduces DC abundance, constrains maturation under immunoregulatory cues, and promotes tolerogenic phenotypes, establishing a suppressive immune niche. These changes blunt responses to immunotherapy but also reveal therapeutic opportunities to restore DC function or relieve inhibitory pathways such as PD-L1 and TGF-β, with the goal of improving clinical benefit.

As previously mentioned, the cirrhosis and HCC milieu is commonly associated with fewer DCs, delayed or incomplete maturation of antigen-presenting subsets, and diminished expression of costimulatory ligands. Together, these changes weaken antigen display and the priming of naive T lymphocytes, implying that releasing microenvironmental brakes could be an effective first step toward rescuing DC activity. Robust antitumor immunity in HCC depends strongly on the cDC1 lineage, noted for cross presentation and licensing CD8⁺ T cells; therefore, preferential restoration or supplementation of cDC1 function is a central avenue to strengthen immunity (117). Furthermore, experimental work shows that inhibitory cues within the tumor bed, including VEGF and IL-10, directly disrupt DC maturation and differentiation. Neutralization of VEGF with VEGF-Trap treatment improves DC development, supporting a strategy that lifts suppression to recover function (118, 119). Given the mechanisms that drive PD-L1 expression on DCs in HCC patients, blocking PD-L1 on TAMs could relieve direct inhibition of effector T cells while reducing negative signaling on DCs themselves, thereby enhancing antigen presentation and co-stimulation. Such a maneuver could serve as a valuable element of combination therapy (120, 121). In parallel, amplifying costimulatory pathways with a bispecific antibody such as DuoBody CD40×4-1BB could offset downregulation of CD86, increase DC-mediated T-cell activation, and expand effector populations, demonstrating another feasible route to activation (122).

Improving the recruitment and spatial distribution of intratumoral DCs is also important. When paired with PD-1 blockade, inhibition of CXCR4-dependent chemotactic defects increases entry of DCs and effector lymphocytes into tumor tissue and augments responses (123). From the perspective of innate sensing, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway directly promotes DC maturation and induces type I IFN programs, offering a potent in vivo trigger of function (124). Iron–manganese (Fe–Mn) bimetal nanovaccines can provoke pyroptosis, releasing damage-associated signals and dsDNA that activate the cGAS-STING pathway, with further potentiation by Mn. This cascade drives type I IFN and inflammatory cytokine production, promotes DC maturation, enhances antigen presentation, and recruits large numbers of CD8⁺ T cells to the tumor, thereby intensifying antitumor responses (125). Agonists of TLR4 and TLR7/8 also stimulate DC maturation and are widely used as vaccine adjuvants or within nanodelivery systems to raise the efficiency of antigen presentation and T-cell priming (126). Advances in nanotechnology now enable co-encapsulation of antigens with STING or TLR agonists and targeted delivery to the tumor bed or draining lymph nodes, focusing on in vivo DC activation and improving the quality of priming (127).

Ex vivo-generated DC vaccines, loaded with tumor antigens and reinfused back into patients, can provide a direct supply of functional antigen-presenting cells. When these vaccines are combined with radiotherapy or necrosis-inducing local procedures such as TACE, the therapy-induced release of tumor antigens can be exploited to amplify systemic immunity. Several clinical trials have already been completed (128, 129), including one in which adding a DC vaccine to cyclophosphamide conditioning and TACE enhanced antigen-specific responses and significantly lengthened survival. Personalized approaches using neoantigens have also shown the capacity to elicit specific CD8⁺ T-cell responses (130). Concurrently, DC vaccines used alone in HCC have shown generally good safety and measurable immunogenicity but modest objective responses, suggesting that future benefit will most likely come from combinations with ICIs, in vivo DC-activating adjuvants, or local therapies (131).

An especially promising strategy involves integrating individualized neoantigen vaccines with in vivo DC activators such as STING/TLR agonists and immune checkpoint blockade. This tripartite design simultaneously addresses the three major limitations of antigen supply, DC activation, and ongoing immune suppression, and may deliver more powerful regimens for patients with cirrhosis-associated HCC (132).

In cirrhosis, strengthening T-cell activity for HCC therapy is best pursued with a layered, multitarget combination strategy. Key objectives include counteracting exhaustion programs, restoring mitochondrial and overall metabolic fitness, dampening suppressive cells and mediators, and refining local delivery to minimize liver toxicity.

Because Tex cells frequently coexpress several immune checkpoints, simultaneous blockade at two or more nodes, such as PD-1 together with TIM-3/LAG-3, liberates CD8⁺ T cells more effectively than PD-1 inhibition alone, with synergistic signals observed in both preclinical systems and early clinical studies (133, 134). However, it is rare for removal of inhibitory receptors alone to fully rescue function. Tex cells also exhibit damaged mitochondria and rewired metabolism. Enforced expression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) increases mitochondrial biogenesis, improves the fitness of CD8⁺ populations, and heightens antitumor efficacy—observations supported in both chimeric antigen receptor T-cell (CAR-T) and tumor-infiltrating lymphocyte models (135, 136). As cytokine support, short courses or locoregional dosing of IL-15, including engineered hyper-IL-15, can expand CD8⁺ effectors and boost their function, with antitumor activity reported in liver metastasis and spontaneous HCC models, suggesting compatibility with ICI therapy or cell-based treatments (137, 138).

Cirrhosis also brings expansion of Tregs and other suppressive myeloid populations, including MDSCs and immunoregulatory TAMs. Selectively depleting or disabling Tregs with low-dose cyclophosphamide can transiently lift the brakes on effector cells, strengthening systemic antitumor responses (139). In parallel, interrupting the myeloid suppressive network—either by reprogramming macrophages through inhibition of colony-stimulating factor 1 (CSF1) or its receptor (CSF1R), or by blocking the recruitment and function of MDSCs—can indirectly enhance T-cell infiltration and effector potency (140).

TGF-β sits at the intersection of fibrosis and immune suppression, making it an attractive target. Small-molecule inhibitors of TGF-β receptor I, such as galunisertib, have shown antitumor signals in early HCC trials and, in animal models, reduce fibrosis-related stromal barriers while improving immune cell infiltration. When combined with sorafenib, this approach has yielded acceptable safety and longer overall survival (141), supporting its inclusion within combinatorial regimens.

Epigenetic modulators, including histone deacetylase (HDAC) inhibitors, can raise tumor immunogenicity, enhance antigen presentation, and synergize with checkpoint blockade. With careful attention to dosing and route, this avenue may further improve outcomes (142). Finally, local and regional immune activation deserves more emphasis. Intratumoral oncolytic viruses as single agents have demonstrated antitumor activity with low systemic toxicity. In HCC, related studies indicate that pairing such local therapy with systemic ICIs can amplify whole-body antitumor immunity (143), offering a practical path to lift the effectiveness of immunotherapy in patients with cirrhosis.

Macrophage reprogramming in cirrhotic livers—a shift that favors tolerance and supports HCC—has made these cells attractive therapeutic targets for boosting responses to immunotherapy. Concurrent inhibition of CCR2 and CCR5 with agents such as cenicriviroc limits the influx of suppressive macrophages and promotes fibrotic regression in hepatic models (144, 145). Signaling through CSF1 and CSF1R maintains M2-skewed phenotypes; blocking CSF1R can lessen TAM-driven immunosuppression and act synergistically with PD-1 blockade (146). Cirrhosis-enriched TREM2⁺CD9⁺ scar-associated macrophages, largely originating from circulating monocytes, contribute to matrix remodeling and immune suppression; anti-TREM2 therapy paired with ICIs restored cytotoxic T-cell activity in preclinical studies (147). The interaction between CD47 on tumor cells and signal regulatory protein alpha (SIRPα) on phagocytes delivers an antiphagocytic signal. Consistently, interrupting this pathway via antibodies against CD47 or SIRPα enhances macrophage engulfment, improves cross-presentation, and augments PD-1 therapy (148, 149). In HCC models, the anti-CD47 antibody B6H12 stimulates macrophage-mediated clearance, restrains tumor growth, and increases chemotherapy efficacy (150). Another innate checkpoint, the CD24–Siglec-10 axis, suppresses myeloid activation, with its blockade lifting myeloid quiescence and strengthening antitumor immunity (151). Kinases of the TAM family, MERTK and AXL, help preserve immunosuppressive TAM programs; inhibitors of these receptors combined with checkpoint blockade show signs of enhanced immune activity (152, 153). Myeloid PI3Kγ functions as a hub for suppressive transcriptional circuits. Inhibition of PI3Kγ with eganelisib repolarizes TAMs and MDSCs toward inflammatory states, restores T-cell function, and can overcome resistance when added to ICI therapy (154). Because persistent TLR4 signaling sustains tolerogenic macrophage states in cirrhosis, TLR4 inhibition reduces immunosuppressive mediators and improves antitumor responses, making it a plausible partner in combination regimens (155).

Macrophage metabolism is also actionable. Restraining lactate production or export—through targets such as lactate dehydrogenase A (LDH-A) or monocarboxylate transporter (MCT)4—can correct suppressive macrophage bioenergetics and heighten the effectiveness of ICI therapy (156). Both hypoxia and pathologic angiogenesis hinder T-cell trafficking and maintain suppressive myeloid cell pools, and pairing anti-VEGF antibodies or angiopoietin-2 (Ang2) blockade with ICIs promotes vascular normalization alongside immune activation. Notably, atezolizumab combined with bevacizumab improved overall and progression-free survival in HCC (157, 158).

As cirrhosis evolves into HCC, persistent inflammation, stromal remodeling, and a locally suppressive immune context within both the tumor niche and surrounding liver tissue reshape neutrophil behavior and polarization, ultimately diminishing T cell-driven antitumor activity. These observations provide a strong rationale for therapeutically modulating neutrophils to improve the performance of immunotherapy, a concept supported by preclinical data.

The generation of NETs represents a key pathogenic output of this lineage. In HCC, such traps facilitate immune escape, in part by fostering Treg infiltration (159). Pharmacologic dismantling with DNase I and inhibition of PAD4 using agents such as GSK484 reduce NET burden and enhance T-cell entry, yielding greater antitumor effects when paired with PD-1 or PD-L1 blockade (37, 160). Consequently, interfering with NET formation or persistence represents an important intervention point against neutrophil-mediated immune evasion (161, 162).

Neutrophil trafficking can also be targeted. In cirrhosis and HCC, chemokines including IL-8 and CXCL family members, together with their receptors CXCR1 and CXCR2, orchestrate marrow egress, circulation, and tumor homing. Inhibition of CXCR2 with AZD5069 combined with ICI therapy expands antitumor neutrophil populations and lowers tumor burden in experimental HCC (163). Thus, blocking the IL-8–CXCR1/CXCR2 axis represents a potent means to increase immunotherapy sensitivity. Resistance to ICI therapy is further linked to the accumulation of low-density or otherwise suppressive neutrophils, such as CD10⁺ALPL⁺ and PLAUR⁺ subsets, which produce ROS, arginase 1, and PD-L1, driving CD8⁺ T-cell exhaustion (112). PLAUR⁺ neutrophils are enriched in nonresponders to PD-1 therapy and predict poor outcomes (41). Selective depletion or functional neutralization of these subsets by targeting markers such as PLAUR or CD10/ALPL may reverse suppression and improve therapeutic efficacy. In parallel, neutrophil-expressed checkpoints and their metabolic wiring remain actionable. Lactate-rich, acidic tumor conditions rewire neutrophils to induce expression of PD-L1, cyclooxygenase 2 (COX-2), and MCT1, further suppressing T-cell function (164). Combining ICI therapy with COX 2 or MCT1 inhibition, or neutrophil-focused PD-L1 blockade, may unlock neutrophils, restoring both neutrophil and T-cell antitumor activity.

Redirecting polarization toward an N1 antitumor program offers another path forward. N1 features are supported by robust IFN signaling, whereas TGF-β promotes conversion to an N2 protumor state (116). Consequently, TGF-β inhibition can enable neutrophil-mediated tumor control. In HCC, low CXCL9 expression frequently coincides with impaired N1 polarization and weaker checkpoint responses (165, 166). Strategies include strengthening the CXCL9 and IFN-γ circuit, deploying small molecules that favor N1 skewing, or engineering neutrophils ex vivo for reinfusion to cooperate with ICIs.

From the perspective of physical barriers, neutrophil elastase contributes to extracellular matrix remodeling and fibrosis in the cirrhosis HCC setting, erecting biochemical and structural obstacles to lymphocyte trafficking (167). Pairing neutrophil-directed therapies with antifibrotic or matrix-modifying approaches, such as TGF-β inhibitors or matrix metalloproteinase modulators, may improve T-cell infiltration and amplify checkpoint efficacy. For clinical translation, a composite biomarker framework that incorporates NET-derived plasma markers such as H3Cit-DNA and MPO-DNA (168), the frequencies of suppressive neutrophil subsets including PLAUR⁺ and CD10⁺ALPL⁺ cells (41, 112), and circulating IL-8 and CXCL9 levels could aid stratification and response prediction (165, 169). Radiomic analyses further suggest that computed tomography-based radiomic NET-associated signatures can forecast responses to immunotherapy in patients with HCC (170).

Future clinical trials should consider concurrent or sequential application of neutrophil-targeting therapies with ICIs, such as CXCR2 inhibition, PAD4 inhibition, or COX-2 combination therapy, supplemented by measures like immune profiling and single-cell sequencing analysis, to enhance the efficacy of HCC immunotherapy. In summary, neutrophils represent a novel target for HCC immunotherapy. Their plasticity, diverse involvement mechanisms, and emerging preliminary clinical evidence confer significant potential to this strategy, warranting further exploration in future combination immunotherapy regimens.