Advances in the Role of Chemokines in Microwave Ablation‐Based Combinatorial Immunotherapy

ABSTRACT

Immunotherapy enhances antitumor immunity to eliminate malignant cells and has great potential to prevent tumor recurrence and distant metastasis. In addition to direct tumor destruction, microwave ablation (MWA) remodels the tumor immune microenvironment (TIME) and induces antitumor immune responses, providing a strong rationale for combination with immunotherapy. As key regulators of immune‐cell trafficking and function, chemokines critically mediate the synergy between MWA and immunotherapy. In this review, we summarize the effects of MWA on the TIME, the central role of chemokine networks in this process, and recent advances in MWA‐based combinatorial immunotherapy, including clinical progress. We also discuss current challenges and future directions to support the optimization of multimodal cancer therapy and improve clinical outcomes.

MWA can initiate antitumor immunity through tumor antigen release and innate immune activation, but iMWA may instead promote an immunosuppressive microenvironment. Combining MWA with immunotherapeutic strategies offers a promising approach to enhance systemic immunity and suppress residual and distant tumors.

Abbreviations

APCs

antigen‐presenting cells

CAR

Chimeric antigen receptor

CTLs

cytotoxic T lymphocytes

DAMPs

damage‐associated molecular patterns

DCs

dendritic cells

HCC

hepatocellular carcinoma

ICIs

immune checkpoint inhibitors

iMWA

incomplete microwave ablation

LAG‐3

lymphocyte activation gene‐3

MDSCs

myeloid‐derived suppressor cells

MWA

microwave ablation

NSCLC

non‐small cell lung cancer

RFA

radiofrequency ablation

TAAs

tumor‐associated antigens

TAMs

tumor‐associated macrophages

TdLNs

tumor‐draining lymph nodes

TIGIT

T‐cell immunoreceptor with Ig and ITIM domains

TILs

tumor‐infiltrating lymphocytes

TIME

tumor immune microenvironment

TME

tumor microenvironment

Tregs

regulatory T cells

1. Introduction

Thermal ablation is a minimally invasive treatment that induces irreversible cell necrosis through thermal stress generated by physical energy conversion and is widely used for the treatment of solid tumors, including hepatic, pulmonary, renal, and thyroid carcinomas [1]. Achieving complete conformal ablation in clinical practice remains challenging due to individual tumor heterogeneity and high‐risk anatomical locations, such as proximity to major blood vessels or vital organs. Incomplete microwave ablation (iMWA) not only precipitates local recurrence but also enhances the invasiveness of residual tumor cells through sublethal thermal stress, thereby accelerating tumor metastasis and progression [2].

Immunotherapies, particularly immune checkpoint inhibitors (ICIs), offer immense potential in preventing recurrence and distant metastasis by reversing immune evasion and reactivating effector T cells within the tumor microenvironment (TME) [3]. MWA induces immunogenic cell death and the release of danger signals, including tumor‐associated antigens (TAAs) and damage‐associated molecular patterns (DAMPs). These signals recruit and activate antigen‐presenting cells (APCs) at the tumor margin, orchestrating robust anti‐tumor responses involving T cells and other immune cells, laying the groundwork for subsequent combinatorial immunotherapies [4].

Dynamic shifts within the chemokine network serve as crucial mediators during the remodeling of the tumor immune microenvironment (TIME). By modulating the expression of chemokines and their cognate receptors within the TME, thermal ablation or cryoablation precisely dictates the landscape of immune cell infiltration to orchestrate anti‐tumor immune responses. Specifically, the CXCL9/10‐CXCR3 interaction represents a critical molecular axis driving the recruitment of effector CD8⁺T cells into the TME [5]. Following MWA, the marked induction of CXCL9 and CXCL10 promotes antitumor immunity [6]. Cryoablation promotes macrophage aggregation and high expression of CXCL10, recruiting T lymphocytes and enhanceing the efficacy of PD‐1 [7]. In contrast, incomplete thermal ablation upregulates the CXCL2/CXCL5‐CXCR2 axis, promoting MDSC recruitment, impairing CD8⁺T cell function, and accelerating immune evasion and malignant progression [8, 9].

Utilizing MWA to initiate locoregional immune responses and modulate chemokine networks fosters a permissive microenvironment for immunotherapy. In turn, leveraging immunotherapeutic agents to amplify chemokine‐mediated anti‐tumor responses overcomes the limitations of monotherapy. This review systematically synthesizes the dynamic crosstalk among MWA, iMWA, chemokine networks, and immunotherapies. Furthermore, it delves into synergistic therapeutic strategies and recent clinical advancements, aiming to provide a novel theoretical framework and practical reference for the comprehensive management of intermediate and advanced‐stage solid tumors.

2. Microwave Ablation

2.1. Technical Mechanism and Clinical Applications of Microwave Ablation

The mechanism of MWA involves the direct delivery of microwave energy, typically at frequencies of 915 or 2450 MHz, into tumor tissue. This electromagnetic radiation induces high‐frequency oscillation of polar molecules, thereby generating intense heat through intermolecular friction. When the local tissue temperature exceeds 60°C, protein denaturation, nucleic acid fragmentation, and organelle disruption occur, ultimately leading to irreversible coagulative necrosis of tumor cells. In contrast, sublethal temperatures of 40°C–60°C may induce apoptosis or promote thermal tolerance, thereby contributing to residual disease and tumor recurrence [10]. Compared with radiofrequency ablation (RFA), MWA exhibits several biophysical advantages, including faster heating, larger ablation zones, and reduced susceptibility to the heat‐sink effect [10, 11].

Currently, MWA is widely used in the clinical management of hepatic, pulmonary, and other metastatic solid tumors and is increasingly recognized as a preferred nonsurgical treatment for early‐stage liver cancer. In patients with solitary early‐stage hepatocellular carcinoma (HCC) measuring 3–5 cm in diameter, MWA achieves 5‐year survival rates comparable to those of laparoscopic liver resection while offering shorter hospital stays and lower healthcare costs [12]. Additionally, MWA has been widely adopted for the treatment of pulmonary metastatic cancer, thyroid microcarcinomas, metastatic breast cancer, bone tumors and so on. The therapeutic value is increasingly being validated in clinical practice (Table 1) [13, 14, 15, 16, 17, 18, 19].

TABLE 1.

Clinical application of MWA in tumor treatment.

Cancer type	Application	Advantages	References
Liver cancer	Isolated tumor, 3–5 cm in size; patients with inadequate liver remnant to tolerate resection, tumor multinodularity, unresectable lesions at difficult anatomical locations	Increased OS and local tumor PFS, low complication rate, less intraoperative blood loss, short operation time and hospital stay	[12]
Thyroid cancer	Papillary Thyroid Microcarcinoma; unifocal papillary thyroid carcinoma	Favorable efficacy with satisfactory safety for the treatment of PTMC	[13]
Breast cancer	Preoperative early‐stage breast cancer	Comparable tumor control effect with breast‐conserving surgery; better cosmetic results	[14]
Renal cancer	T1 Renal Cell Carcinom	High efficacy rates and few complications	[15]
Prostate cancer	Low‐ or intermediate‐risk PC	Complete necrosis evidence within the ablation zone; secure and feasible	[16]
Bone Tumors	Bone Tumors; metastatic osseous pain	A low rate of complication and no late recurrence; relieve pain to improve the quality of life	[17, 18]
Lung cancer	NSCLCs with synchronous solitary extracranial metastases	Lower LTP, higher OS, and generally lower DFS	[19]

Despite its efficacy in eliminating tumor cells, MWA is associated with a relatively high rate of local recurrence. This limitation is largely attributable to the relatively weak immune response elicited by MWA, which is insufficient to fully eradicate minimal residual disease. Moreover, post‐ablation upregulation of immune checkpoint molecules, such as programmed death‐ligand 1 (PD‐L1), further facilitates tumor immune evasion [20]. Additionally, the clinical consequences of iMWA are profound, as it not only increases the invasive and metastatic potential of residual tumor cells but also fosters an immunosuppressive microenvironment, ultimately leading to higher recurrence rates and poorer overall survival [21].

2.2. Modulatory Effects of MWA on the Tumor Immune Microenvironment

Tumor cells evade immune surveillance by establishing an immunosuppressive network characterized by the recruitment of tumor‐associated macrophages (TAMs), regulatory T cells (Tregs), and myeloid‐derived suppressor cells (MDSCs), the secretion of inhibitory cytokines such as interleukin‐10 and transforming growth factor‐β, and the upregulation of immune checkpoint molecules [22]. MWA generates necrotic tumor debris that may serve as an in situ vaccine, thereby helping reverse the pre‐existing immunosuppressive state of the TIME. The main mechanisms underlying MWA‐induced antitumor immune activation are summarized below (Figure 1).

FIGURE 1.

Distinct immunological consequences of MWA and iMWA. MWA induces coagulative necrosis and complete tumor destruction, resulting in the release of tumor‐associated antigens (TAAs), ATP, heat shock proteins (HSPs), and high‐mobility group box 1 (HMGB1). Tumor‐derived DNA further activates innate immune sensing through the cGAS‐STING‐TBK1/IRF3 pathway, promoting type I interferon (IFN‐I) production. These signals enhance DC activation and antigen presentation, leading to the priming and expansion of CD8⁺ T cells. In addition, IFN‐γ‐mediated activation of the NF‐κB/JAK‐STAT1 signaling axis promotes CXCL9/10 production and recruitment of CXCR3⁺CD8⁺T cells, thereby amplifying systemic antitumor immunity and contributing to abscopal tumor control. In contrast, iMWA leaves residual tumor cells in the peri‐ablational zone exposed to sublethal heat stress. This condition promotes epithelial‐mesenchymal transition (EMT), tumor cell proliferation, migration, and invasion, and is associated with increased expression of protumor factors, including CXCL2, CXCL5, IL‐6, VEGF, and HGF. These changes drive the recruitment of CXCR2⁺ monocytes and CXCR2⁺MDSCs, as well as the expansion of immunosuppressive cell populations such as Tregs, TAM2, and SPP1+ TAMs. Meanwhile, CD8⁺T cells and NK cells are suppressed, leading to the establishment of an immunosuppressive microenvironment that facilitates tumor progression and distant metastasis. Some of these immunosuppressive changes may be reversed by anti‐Gr‐1 antibody treatment.

2.2.1. Release of TAAs and DAMPs to Initiate Immune Responses

MWA‐induced tumor necrosis causes the extensive release of TAAs and DAMPs, including high‐mobility group box 1, adenosine triphosphate, heat shock proteins, and uric acid, which are then recognized, internalized, and processed by APCs, including macrophages and dendritic cells (DCs), to initiate systemic immune activation. Furthermore, MWA‐induced cellular apoptosis and necrosis facilitate the release and subsequent presentation of intracellular tumor antigens [4]. Tumor‐derived DNA released from damaged tumor cells is sensed by the cytosolic cGAS‐STING pathway, which subsequently activates TBK1‐IRF3 signaling and induces Type I interferon production, thereby further driving DC activation [23, 24]. Together, TAAs and DAMPs prime DC‐mediated adaptive immunity by promoting the activation of CD8⁺T and CD4⁺T cells, thereby supporting durable antitumor immune responses.

2.2.2. Modulation of the Immune Cell Infiltration Landscape and Cytokine Networks

Following MWA, the TIME undergoes substantial remodeling, characterized by altered immune cell composition, abundance, functional states, and cytokine profiles. Specifically, activated CD8⁺T and CD4⁺T cells increase in both locoregional tissues and peripheral blood. Along with elevated IFN‐γ and TNF‐α levels, these changes drive the TIME toward an antitumor T‐helper 1 (Th1) phenotype [4, 25]. Furthermore, MWA reduces the infiltration and function of immunosuppressive cells, such as Tregs and MDSCs, thereby alleviating the immunosuppressive milieu of the TIME [26]. Moreover, MWA induces enrichment of chemokine signaling pathways, particularly the CXCL10/CXCR3 axis, thereby further promoting immune cell recruitment. Concurrently, it increases PD‐L1 expression on both tumor cells and immune cells [6], providing a strong rationale for combining MWA with ICIs.

2.2.3. Modulatory Effects of iMWA on the Tumor Immune Microenvironment

iMWA‐induced sublethal thermal stress drives metabolic reprogramming in residual tumor cells and promotes aberrant recruitment of immunosuppressive cells, thereby fostering an immunosuppressive TIME that accelerates tumor recurrence and immune evasion [20]. Sublethal thermal stress stabilizes hypoxia‐inducible factor‐1α, thereby reinforcing aerobic glycolysis in residual tumor cells. This metabolic reprogramming promotes epithelial‐mesenchymal transition and thermal tolerance, while also markedly impairing the proliferation and cytotoxic function of cytotoxic T lymphocytes (CTLs), ultimately contributing to HCC recurrence and metastasis following thermal ablation [27]. Furthermore, iMWA increases the levels of interleukin‐6, hepatocyte growth factor, and vascular endothelial growth factor in both liver tissue and serum, thereby directly promoting rapid residual tumor growth [28]. Incomplete thermal ablation induces CEBPD‐dependent CXCL2 secretion, which promotes the chemotactic recruitment of CXCR2+ monocytes. Moreover, elevated CXCL2 drives the accumulation of SPP1+ TAMs via the CXCL2/STAT3/SPP1 axis and enhances tumor cell invasiveness. Following iMWA, CXCL5 is markedly upregulated, promoting the recruitment of neutrophils and monocytes and thereby expanding immunosuppressive cell populations, including MDSCs, Tregs, and M2‐like tumor‐associated macrophages (TAM2s) [8]. Concurrently, the proportions of CD4⁺ T cells, cytotoxic T lymphocytes (CTLs), natural killer cells, and M1‐like tumor‐associated macrophages (TAM1s) are significantly reduced, an effect that can be reversed by anti‐Gr‐1 antibody treatment [29].

3. Synergistic Mechanisms and Progress of MWA Combined With Immunotherapy

3.1. MWA Combined With Immune Checkpoint Inhibitors

Both preclinical and clinical studies support the combination of MWA and ICIs as a promising therapeutic strategy. Mechanistic investigations further indicate that MWA combined with lymphocyte activation gene‐3 (LAG‐3) blockade remodels the TME, increases the ratio of TAM1s to TAM2s, and enhances the proliferation and effector function of CD8⁺T cells [30]. Furthermore, combining MWA with anti‐PD‐1 or anti‐CTLA‐4 antibodies not only increases intratumoral CD8⁺T cell infiltration but also shifts the cytokine profile by increasing Th1‐type cytokines and decreasing Th2‐type cytokines [31]. In the MC38 tumor‐bearing mouse model, MWA combined with T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade reverses CD8⁺T cell exhaustion, remodels myeloid cell populations, and ultimately suppresses tumor growth [32]. These mechanisms have been validated across multiple solid tumor models. For example, in a non‐small cell lung cancer (NSCLC) rechallenge model, this combination strategy enhanced T‐cell function within tumor‐draining lymph nodes (TdLNs) [33]. Similarly, in a breast cancer model, combination therapy significantly prolonged the survival of tumor‐bearing mice by strengthening antigen‐specific immune responses [34]. As a streptococcus‐derived immunostimulant, OK‐432 remodels the TIME by enhancing intratumoral CD8+ T‐cell infiltration, thereby shifting the immune milieu toward Th1 polarization. Beyond conventional ICI‐based regimens, MWA combined with OK‐432 effectively activates innate immunity and promotes the production of antitumor cytokines, including IL‐18, IL‐2, and IL‐12 [35].

These encouraging findings have been preliminarily supported in clinical settings. Studies in early‐stage breast cancer have shown that preoperative camrelizumab plus MWA promotes clonal expansion and immune memory formation of peripheral CD8⁺T cells. In addition, this regimen appears safe and feasible [36]. In patients with HCC, the combination of MWA, camrelizumab, and apatinib significantly prolongs both progression‐free survival and overall survival, while concurrently boosting anti‐tumor immune responses [37].

3.2. MWA Combined With CAR‐T Cell Therapy

Chimeric antigen receptor (CAR) T‐cell therapy exhibits constrained therapeutic performance in solid tumor management, largely attributable to the complex immunosuppressive tumor TME and the shortage of tumor‐specific targets on tumor cells. Preclinical studies suggest that MWA can effectively reverse the locoregional immunosuppressive state and thereby enhance the efficacy of CAR‐T therapy in solid tumors. In humanized mouse models, MWA promotes CAR‐T‐cell activation, infiltration, and long‐term persistence within the tumor bed. In addition, it enhances mitochondrial oxidative metabolism in CAR‐T cells, leading to marked tumor growth inhibition [38]. In an HCC model, secreting CAR‐T (sCAR‐T) cells engineered to secrete signal regulatory protein $\alpha$(SIRP $\alpha$) act in concert with MWA, which recruits macrophages to unablated lesions. These sCAR‐T cells block the CD47‐SIRPα axis, repolarize M2‐like TAMs, and upregulate pro‐inflammatory chemokines such as CCL3, CCL4, and CXCL2. Together, these effects overcome immune evasion associated with tumor antigen heterogeneity by enhancing macrophage‐mediated phagocytosis and CAR‐T‐cell cytotoxicity, ultimately eliciting a robust abscopal effect at distant tumor sites [39].

3.3. Application of Nanomaterials in Combinatorial Therapies

Although the combination of MWA and immunotherapy synergistically activates both locoregional and systemic immunity, thereby inducing abscopal effects, uncertainty in ablation margins and the resulting occurrence of iMWA frequently lead to tumor recurrence. Nanomaterials provide a promising technological platform to address this clinical bottleneck by enabling precise targeted delivery, controlled drug release, and extensive modulation of the TIME (Table 2) [40, 41, 42, 43, 44].

TABLE 2.

Advances on the application of nanotechnology in MWA and immunotherapy.

Name	Composition	Function	References
Mn‐Zr MOF	Mn, Zr, DAC	Promote the thermal effects of microwave radiation, cause thermal and oxidative damage to cancer cells, enhance the efficacy of anti‐PD‐1 therapy	[40]
MnCa‐MOF	MnCa, Pyrotinib, immunosuppressant PD‐1/PD‐L1 inhibitor 2	Promote the cGAS‐STING pathway, ameliorate the tumor immunosuppressive microenvironment; down‐regulates EGFR and its downstream pathways PI3K/AKT/mTOR and MAPK/ERK signaling pathways to maximize the therapeutic effect of immune checkpoint blocking	[41]
IPI549@Gel	IPI549, aPD‐L1	Disrupt the immunosuppressive niche and subsequently improve ICB‐mediated antitumor immune response; inhibit tumor progression and metastasis	[42]
smDV‐aCTLA‐4	smDV, aCTLA‐4	Promote antigen presentation and immune checkpoint suppression to activate CTLs and improve the safety of anti‐CTLA‐4 antibody. Moreover, the anti‐tumor efficacy of CTLs be further enhanced by anti‐programmed death 1 (aPD‐1) antibody	[43]
LOX‐MnO2@Gel	Lactate oxidase(LOX), MnO2	Transform the immunosuppressive postablative TME into an immunocompetent one and synergizes with ICB therapy to significantly inhibit residual HCC growth and lung metastasis	[44]

Various classes of nanomaterials exhibit distinct mechanistic advantages in combination therapy. Among them, metal–organic frameworks (MOFs), a novel class of nanomaterials composed of metal ions and organic ligands, are characterized by a large specific surface area, high porosity, and exceptional drug‐loading capacity [45]. For example, a nanoparticle system loaded with the DNA methylation inhibitor decitabine serves as a potent MWA sensitizer. It not only enhances microwave‐induced thermal effects and promotes reactive oxygen species generation, thereby significantly upregulating Gasdermin E expression and inducing tumor cell pyroptosis, but also improves the efficacy of anti‐PD‐1 therapy, providing a novel therapeutic strategy for bladder cancer [40]. In tumor vaccine development, DC‐derived extracellular vesicles show considerable promise; however, their clinical efficacy is often constrained by inadequate antigen presentation and increased expression of immune checkpoint molecules, such as PD‐1 and CTLA‐4, on activated T cells [46]. Incorporating ICIs into this regimen may effectively address this limitation. Studies have shown that small nanovesicles derived from mature DCs and conjugated with anti‐CTLA‐4 antibodies significantly enhance the infiltration of both endogenous CTLs and adoptively transferred tumor‐infiltrating lymphocytes (TILs), thereby enabling complete eradication of residual HCC cells following iMWA [43]. Furthermore, injectable hydrogel systems have shown strong potential for locoregional therapeutic co‐delivery and metabolic reprogramming of the TIME. In particular, hydrogel scaffolds designed for in situ co‐delivery of the PI3Kγ inhibitor IPI549 and anti‐PD‐L1 antibodies significantly decrease the accumulation of immunosuppressive cell populations while enhancing CD8⁺T cell and memory T cell infiltration [42]. The synergistic mechanisms and recent research progress of MWA combined with immunotherapy are summarized in Figure 2.

FIGURE 2.

MWA‐based combinatorial immunotherapeutic strategies. MWA promotes the release of TAAs, DAMPs, and IFN‐I, activates dendritic cells, and reshapes the tumor immune microenvironment, thereby providing a basis for combination immunotherapy. MWA can be combined with immune checkpoint inhibitors, immunostimulatory agents such as the bacterial‐derived immunostimulant OK‐432, macrophage‐targeting strategies, CAR‐T‐related approaches, and nanomaterial‐ or biomaterial‐based platforms. These combinations enhance effector T‐cell activation, cytokine production, immune‐cell recruitment, macrophage repolarization, pyroptosis, immune memory, and systemic antitumor responses, ultimately contributing to the inhibition of residual tumors and the induction of abscopal effects.

4. The Role of Chemokines in MWA Monotherapy and Combinatorial Immunotherapy

4.1. Immune Activation of the Chemokine Network by MWA

The activity of the CXCL9/10‐CXCR3 axis serves not only as an important indicator of the immune status of the TIME but also as a key determinant of whether MWA combined with PD‐1/PD‐L1 blockade can elicit systemic abscopal antitumor effects [47]. Studies have demonstrated that in mouse models of colorectal liver metastasis, the combinatorial administration of MWA and PD‐L1 inhibitors achieves synergistic efficacy via the IFN‐γ/CXCL9 cytokine axis. This combined regimen not only promotes DCs' maturation and antigen presentation within TdLNs but also significantly augments the infiltration of activated CD8⁺T cells and upregulates IFN‐γ expression. The elevated IFN‐γ further stimulates CXCL9 secretion, thereby reinforcing the targeted recruitment of effector T cells and establishing an anti‐tumor positive feedback loop [48]. Furthermore, MWA treatment significantly upregulates CXCL10 expression in TAMs and CXCR3 expression in T cells. In animal models, CXCL10 knockout reverses the survival benefits conferred by ablation and accelerates tumor growth [6]. Moreover, the administration of exogenous cytokines alongside MWA can further fortify the anti‐tumor phenotype of the chemokine network. The combination of MWA and IL‐21 therapy alters the immune status of the TME by significantly upregulating anti‐tumor chemokines, including CXCL9 and CXCL10, costimulatory molecules in macrophages, while enhancing CCL2 expression in TAM2s. Consequently, this potentiates the effector functions of CD8⁺T cells and inhibits tumor progression [49]. Building upon this, the combination of MWA with novel immune checkpoint inhibitors can further amplify the activation of this chemokine network. For instance, combining MWA with anti‐LAG‐3 monoclonal antibodies significantly enhances the numerical and spatial interactions between myeloid cells and CD8⁺ T cells. By robustly activating the IFN and CXCL signaling pathways, this combined strategy enhances the targeted recruitment of effector T cells by myeloid cells, ultimately elevating the proportions of CD45⁺ cells, CD4⁺ cells, and TILs in the microenvironment, thereby effectively shrinking tumor volume [30]. Similarly, the combination of MWA and TIGIT blockade reshapes the T cell‐associated chemokine signaling landscape. This strategy significantly increases the expression of pro‐inflammatory and T‐cell‐recruiting chemokines, including CCL5, CXCL9, and CXCL16, while reducing immunosuppressive chemokines such as CCL2 and CCL7. Through this multidimensional remodeling of the chemokine network, the combination achieves marked tumor growth suppression and prolongs survival [32]. In summary, targeted activation of the chemokine network is a central mechanism underlying the synergistic antitumor efficacy of MWA‐based combination therapies, thereby transforming MWA from a local ablative approach into a systemic antitumor modality.

4.2. Chemokine Network Dysregulation and Immunosuppression Induced by iMWA

The aberrant activation of the CXCL5‐CXCR2 axis plays a pivotal role in driving tumor angiogenesis and malignant progression [50]. In HCC models, iMWA directly elevates the expression of CXCL5 and CXCR2, orchestrating the massive chemotactic recruitment of MDSCs [8]. In vivo studies and cytokine profiling have shown that MMP‐9, CXCL2, and IL‐1α are significantly upregulated in the peritumoral regions of residual lesions after MWA. This molecular shift promotes a pro‐inflammatory and pro‐metastatic microenvironment, thereby providing a strong rationale for optimizing MWA regimens and preventing post‐ablation recurrence through targeted inhibition of specific chemokine‐associated pathways [51]. In summary, the aberrant tissue stress induced by iMWA activates immunosuppressive chemokine signaling to recruit an abundance of suppressive cells like MDSCs, thereby accelerating immune evasion and tumor recurrence. This underscores the urgent clinical imperative to combine ablation therapies with specific chemokine pathway antagonists, aiming to fundamentally reverse this hostile microenvironment.

5. Combinatorial Strategies of Microwave Ablation and Immunotherapy Based on Chemokine‐Targeted Interventions

5.1. Fortifying Anti‐Tumor Chemokine Signals to Promote Effector Cell Infiltration

Although the combination of MWA with PD‐1/PD‐L1 blockade represents the most extensively investigated combinatorial regimen to date, targeted interventions against specific chemokines can significantly overcome its therapeutic bottlenecks. Studies have demonstrated that combining MWA with anti‐PD‐L1 therapy activates the NF‐κB/JAK‐STAT1 signaling pathways within the tumor tissue, promoting IFN‐γ and TAM1s polarization and inducing robust CXCL9 secretion by tumor cells. This signaling cascade potently drives the deep intratumoral infiltration of CD8⁺T cells and Th1 cells, reversing T cell exhaustion to consequently suppress tumor growth and prolong overall survival in murine models. Notably, either genetic deletion of Cxcl9 or functional blockade of CXCL9 completely abolishes the antitumor efficacy of this combination regimen, highlighting the essential regulatory role of CXCL9 in this synergistic process [48]. Furthermore, immune adjuvants such as polyinosinic‐polycytidylic acid, when combined with anti‐PD‐L1 therapy, can effectively enhance CXCL9 and CXCL10 secretion. This chemokine upregulation promotes recruitment of CD4⁺T and CD8⁺T cells, thereby providing a strong rationale for the adjuvant use of immunostimulatory agents after MWA to strengthen the pro‐inflammatory chemokine network [52].

5.2. Antagonizing Immunosuppressive Chemokine Signals to Remodel the Tumor Microenvironment

Conversely, inhibition of pro‐tumorigenic chemokine receptor signaling can effectively disrupt the recruitment of immunosuppressive cells, thereby potentiating the immune‐activating effects of thermal ablation. Preclinical studies have demonstrated that sublethal heat stress induces CXCL2 expression in tumor cells, which in turn promotes tumor progression. Moreover, CXCR2 inhibitors independently suppress post‐ablation tumor progression and synergize with ICIs to enhance antitumor efficacy [9]. The CCL2‐CCR2 axis is a central pathway governing recruitment of TAMs and MDSCs. Existing relevant studies have primarily validated the independent immunomodulatory and antitumor effects of CCR2 blockade, providing indirect preclinical evidence for its combined application with MWA. In HCC models, genetic deletion of Ccr2 or pharmacological inhibition of CCR2 not only suppresses recruitment of inflammatory monocytes and TAM2s polarization, but also remodels the immunosuppressive TME and reinvigorates CD8⁺T‐cell‐mediated antitumor immunity [53]. Furthermore, both pharmacological CCR2 antagonism and loss of tumor‐cell‐derived CCL2 enhance the antitumor efficacy of PD‐1 blockade, indicating a potential salvage approach for residual tumors after iRFA [54]. Likewise, the peritumoral microenvironment after MWA often shifts toward a pro‐inflammatory and pro‐metastatic state, promoting invasion and immune evasion of residual tumor cells. Accordingly, targeting these pro‐tumorigenic chemokine‐related networks represents a promising strategy for improving the therapeutic performance of MWA [51]. For example, CCR8‐targeted antibodies selectively deplete intratumoral Tregs while sparing peripheral Tregs. Although this strategy shows limited antitumor efficacy as monotherapy, it synergizes with anti‐PD‐L1 therapy to relieve immune suppression and inhibit tumor growth. However, its application in MWA‐based combination therapy remains prospective [55].

6. Conclusion and Future Perspectives

Post‐ablation hypoxia and thermal stress remodel the TME, resulting in transient and limited antitumor immunity. Therefore, combining MWA with immunotherapy, including ICIs, CAR‐T cell therapy, and immunostimulatory agents, has emerged as a promising strategy for solid tumors. In this setting, the chemokine network acts as a central hub regulating immune‐cell migration and activation. Targeting this network may help overcome post‐ablation immune tolerance and promote the durable conversion of local tumor destruction into systemic antitumor immunity. Future research should focus on three priorities: strengthening pro‐inflammatory pathways such as CXCL9/10/11‐CXCR3 while blocking the recruitment of MDSCs and TAM2s; improving drug delivery and controlled release through nanocarriers, injectable hydrogels, and engineered oncolytic viruses; and integrating single‐cell sequencing with spatial multi‐omics to define chemokine‐mediated interactions within the TME. Overall, the chemokine network is a key regulator of MWA‐induced antitumor immunity and a promising target for improving the clinical efficacy of MWA‐based combination therapy.

Author Contributions

Ruijie An: writing – original draft, data curation. Ningning He: writing – review and editing, conceptualization, funding acquisition. Wendong Gu: writing – review and editing, conceptualization.

Funding

This work was supported by 2025 Annual Changzhou Municipal Health Commission Science and Technology Project Initiation Project (Youth Project), QN202511. Jiangsu Graduate Research and Practice Innovation Program, SJCX23_2032.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are openly available in pubmed at https://pubmed.ncbi.nlm.nih.gov/, reference number 55.