Tumor microenvironment-guided targeted and immunotherapy in anaplastic thyroid cancer: a literature review from preclinical models to clinical translation

Introduction

Anaplastic thyroid cancer (ATC) represents one of the most aggressive and lethal malignancies, accounting for less than 2% of all thyroid cancers but contributing disproportionately to thyroid cancer-related mortality (1). Characterized by rapid progression, extensive local invasion, and distant metastasis, ATC demonstrates profound resistance to conventional therapies with a median overall survival (mOS) of merely 3–6 months (2). The unique composition of the ATC tumor microenvironment (TME) remains a major barrier to treatment efficacy (3).

Growing insights into ATC molecular pathology have revitalized therapeutic strategies. In 2018, the USA Food and Drug Administration (FDA) approved dabrafenib and trametinib combination for patients with unresectable or metastatic ATC harbouring the BRAF V600E mutation, marking the first targeted therapy approved for ATC (4,5). However, even among BRAF-mutant patients, response durability remains limited due to complex resistance mechanisms (6,7).

The TME comprises diverse cellular components (immune cells, fibroblasts, endothelial cells) and non-cellular components [extracellular matrix (ECM), growth factors, cytokines] (8). These components interact dynamically with tumor cells to shape progression and therapeutic response. The ATC TME is profoundly immunosuppressive and metabolically reprogrammed, fostering immune evasion and treatment resistance (9). Compared with differentiated thyroid cancer (DTC), ATC exhibits significant enrichment of immunosuppressive populations, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) (10-12). These populations collectively impair antitumor immunity. The microenvironment features high programmed death-ligand 1 (PD-L1) expression, dense cancer-associated fibroblasts (CAFs) that impede immune infiltration, aberrant angiogenesis, and extensive stromal remodelling (13-15). Immunosuppressive cytokines such as IL-10 and TGF-β promote immune escape and sustain a “cold” immune phenotype, diminishing immune checkpoint inhibitors (ICIs) (16).

Recent studies suggest that TME-directed therapies hold unprecedented promise for ATC management. Hamidi et al. [2024] demonstrated that triplet therapy with dabrafenib, trametinib, and pembrolizumab extended mOS to 17 months in BRAF V600E-mutant ATC patients, and up to 63 months in those receiving neoadjuvant treatment (17). Similarly, Cabanillas et al. [2024] reported that personalised immuno-targeted therapy based on molecular subtyping achieved 19 months mOS (18). These advances indicate that TME understanding and modulation may be pivotal to overcoming therapeutic resistance.

This review systematically examines advances over the past five years in ATC-targeted and immunotherapy research, from preclinical models (animal experiments) to clinical trials, focusing on TME-targeting strategies and their translational potential. We analysed 82 animal studies and 47 clinical investigations to evaluate mechanisms and efficacy of TME-directed monotherapies and combination regimens, aiming to provide a foundation for understanding ATC biology and advancing therapeutic strategies. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1882/rc).

Methods

The literature search followed a systematic approach as outlined in Table 1. A comprehensive literature search was conducted in PubMed and Web of Science Core Collection databases from January 1, 2020 to August 1, 2025. Search terms included ATC, targeted therapy, immunotherapy, and TME (detailed search strategies in Table S1). English-language peer-reviewed articles reporting original preclinical or clinical data were included. Studies were categorized into preclinical targeted therapy (n=69), clinical targeted therapy (n=19), preclinical immunotherapy (n=13), clinical immunotherapy (n=6), and clinical combination therapy (n=22) groups for narrative synthesis.

Composition and characteristics of the TME in ATC

Cellular components

As illustrated in Figure 1, the primary cellular constituents of the ATC TME include Tregs, TAMs, CAFs, and sparsely infiltrating CD8⁺ effector T cells. These cells interact through a complex signalling network that collectively drives tumor progression (9,19,20). T cell exhaustion is one of the most prominent features. It is marked by high expression of exhaustion markers such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) on CD8⁺ T cells, alongside an increased proportion of CD4⁺ Tregs. These findings suggest a TME characterized by persistent antigen stimulation and profound immune suppression (21,22).

Figure 1 Schematic representation of the cellular and non-cellular components of the ATC TME. ATC, anaplastic thyroid cancer; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HGF, hepatocyte growth factor; IL-6, interleukin-6; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PDGF, platelet-derived growth factor; TAM, tumor-associated macrophage; TGF, transforming growth factor; TME, tumor microenvironment; VEGF, vascular endothelial growth factor.

Although T cell function is impaired, the high PD-1 expression offers a theoretical rationale for the application of ICIs, particularly PD-1/PD-L1 antibodies. Furthermore, Han et al. [2024] identified prominent tertiary lymphoid structures (TLSs) and enriched C-X-C motif chemokine ligand 13 (CXCL13)⁺ T cells in ATC through transcriptomic profiling of 226,066 cells at single-cell resolution (13). These features are associated with increased sensitivity to immunotherapy.

TAMs are among the most abundant immune cells in the ATC microenvironment. Choi et al. [2024] found that M2-polarised TAMs promote tumor progression via carboxypeptidase A4 (CPA4) secretion, and genetic deletion of CPA4 completely inhibited tumor formation (14). Liu et al. [2024] uncovered a signalling axis involving C5a receptor 1(C5AR1)—miR-335-5p—toll-like receptor 1/2 (TLR1/2)—myeloid differentiation primary response 88 (MyD88), which regulates TAM-mediated metastasis in ATC (23). Liu et al. [2022] provided a comprehensive review of the multifaceted roles of TAMs in thyroid cancer TME (24).

CAFs are key stromal components of the ATC TME. Han et al. [2024] identified an ATC-specific CAF subpopulation, comprising 63.6% of all CAFs, characterised by high expression of fibroblast activation protein (FAP), α-smooth muscle actin (ACTA2), and platelet-derived growth factor receptor β (PDGFRB) (13). CAFs facilitate tumor progression and immune suppression by secreting cytokines such as IL-6, CXCL12, and hepatocyte growth factor (HGF). Moreover, they produce abundant ECM proteins, including fibronectin and type I collagen, and release matrix remodelling enzymes such as matrix metalloproteinase 2 (MMP2) and MMP9 to reshape the TME (25-27).

Endothelial cells in ATC display abnormal proliferation and dysfunction. Iesato et al. [2023] demonstrated that lenvatinib suppresses ATC growth by targeting tumor-associated pericytes, underscoring the critical role of the vascular niche in ATC therapy (28). Wang et al. [2020] developed a vascular endothelial growth factor (VEGF) antibody combined with mitochondria-targeted photothermal therapy, significantly enhancing treatment efficacy through synergistic anti-angiogenic and tumor-ablative mechanisms (29). The vascular architecture in ATC is disorganised, with increased permeability and aberrant perfusion. These abnormalities not only promote tumor growth and metastasis but also lead to hypoxia, further driving pro-angiogenic signalling and perpetuating a vicious cycle.

Non-cellular components

The ECM undergoes substantial remodelling in ATC. Liu et al. [2022] showed that lysyl oxidase (LOX) promotes proliferation and metastasis by activating bone morphogenetic protein 1 (BMP1), while its inhibition by β-aminopropionitrile (BAPN) significantly reduced tumor progression (30). Mi et al. [2024] revealed aberrant activation of the glutamyl-prolyl-tRNA synthetase (EPRS)—activating transcription factor 4 (ATF4)—collagen type I alpha 1 chain (COL1) axis in ATC (31). The activation results in excessive collagen deposition, which could be reversed by halofuginone to suppress tumor growth. Yoshida et al. [2020] found that membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed in 85.3% of ATCs and facilitates invasion by degrading collagen matrix (32). A systems analysis by Xia et al. [2024] showed that ECM-related pathways are commonly activated in ATC. Increased ECM density and stiffness not only promote invasion but also hinder drug delivery (33).

Growth factors and cytokines constitute a key regulatory network within the ATC TME. Both tumor and stromal cells produce angiogenic factors such as VEGF-A, PDGF-BB, and fibroblast growth factor 2 (FGF2). Yamazaki et al. [2020] reported that FGF receptor 4 (FGFR4) expression in tumor cells correlates with lenvatinib sensitivity (34). Pro-inflammatory signalling axes form a complex intercellular communication network among tumor cells, TAMs, and CAFs (35-39). These axes include IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), IL-8/C-X-C motif chemokine receptor 1/2 (CXCR1/2), and tumor necrosis factor α (TNF-α)/nuclear factor κB (NF-κB).

The metabolic microenvironment of ATC is marked by profound reprogramming. Tumour cells exhibit a strong Warburg effect, with elevated expression of glucose transporter 1 (GLUT1) and hexokinase 2 (40-42). Yang et al. [2024] found that shikonin inhibits pyruvate kinase M2 (PKM2) and induces ferroptosis, thereby suppressing ATC growth (42). Davidson et al. [2022] demonstrated that glycogen phosphorylase inhibition selectively kills ATC cells (43). Lactate produced by tumor cells not only acidifies the microenvironment and impairs T cell function but is also transported via monocarboxylate transporter 1 (MCT1) into CAFs and endothelial cells, fuelling a metabolic symbiosis (44).

TME heterogeneity and spatial distribution

Single-cell and spatial transcriptomic technologies have unveiled the remarkable heterogeneity of the ATC TME. Liao et al. [2025], using spatial transcriptomics, mapped the spatial architecture of the TME during thyroid cancer progression and identified distinct immune-activated and immune-suppressed regions within ATC (45). This spatial heterogeneity is not only observed across patients but is also evident within different regions of the same tumor, underscoring the necessity of personalised therapeutic strategies.

Comparison with DTC

The TME in ATC is fundamentally distinct from that in DTC. In contrast to DTC, ATC displays a profoundly remodeled TME. This includes stronger immunosuppression marked by PD-L1 expression and M2-TAM infiltration, more active angiogenesis and stromal remodeling via VEGF, LOX, and MMPs, and a greater reliance on Warburg metabolism (21,24,40,46). These differences partially account for the marked disparity in prognosis between the two diseases and provide a rationale for tailored therapeutic approaches.

In summary, the TME in ATC comprises complex cellular and non-cellular components and is defined by profound immunosuppression, abnormal angiogenesis, extensive stromal remodelling, and unique metabolic features. A deeper understanding of these characteristics is critical for the development of effective therapeutic strategies.

Preclinical and clinical research advances

We systematically reviewed and analysed studies on targeted and immunotherapeutic interventions for ATC published between 2020 and 2025. These studies investigated various therapeutic approaches and molecular targets (14,43,47-69). Additional preclinical studies explored novel therapeutic mechanisms (28,30,31,70-87). Further studies examined resistance strategies (29,42,88-108). We also included 19 clinical targeted therapy studies (5,6,34,109-124), 13 preclinical immunotherapy studies (13,15,23,125-134), 6 clinical immunotherapy studies (21,135-139), and 22 clinical combination therapy studies (17,18,140-159). Detailed information from all included studies is provided in the Tables S2-S6.

Targeted therapeutic strategies and advances

Molecular mechanisms and preclinical discoveries

As shown in Table 2, preclinical studies over the past five years have evolved from targeting single pathways to multidimensional interventions based on the TME, establishing a systematic therapeutic framework centred on “tumor cells-microenvironment-resistance mechanisms”.

The field has expanded from classical pathways to novel targets. The BRAF/MEK axis remains a major focus, but strategies are being continuously refined. Lin et al. [2025] demonstrated that the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor BAY 1895344 significantly suppresses tumor growth in BRAF-mutated ATC (78). A more pivotal breakthrough came from Gunda et al. [2023], who found that axitinib not only inhibits VEGF receptor (VEGFR) but also targets aurora kinase B (AURKB). This multi-target strategy outperformed traditional BRAF/MEK dual therapy in BRAF-mutated models (63). Meanwhile, entirely new therapeutic targets have emerged. Mannino et al. [2025] developed BAY-293, an inhibitor of son of sevenless homolog 1 (SOS1), a downstream effector of KRAS, offering an indirect targeting strategy for KRAS-mutant ATC (87). For BRAF wild-type tumors, Diaz et al. [2024] identified the Wnt/β-catenin pathway as a potential alternative target (52).

The TME plays a crucial role in ATC aggressiveness, driving the development of multi-layered interventions. In angiogenesis targeting, tyrosine kinase inhibitors (TKIs) have been enhanced with innovative delivery platforms. Zhang et al. [2025] designed a nanocapsule that co-delivers anlotinib and iodine-131 (I-131) (106). This approach effectively combines targeted radiotherapy with enhanced tumor uptake and apoptosis induction.

In stromal remodelling, Liu et al. [2022] demonstrated that ECM stiffening via the LOX/BMP1 axis promotes tumor invasion (30). Intervention with BAPN offers a novel approach to soften the tumor stroma. These findings highlight a critical insight: eradicating tumor cells alone is insufficient. Modifying the surrounding microenvironment is equally essential.

Resistance remains the greatest challenge in targeted therapy. Multiple studies have explored strategies to overcome this obstacle. Ma et al. [2025] identified cyclin-dependent kinase 2 (CDK2) as a key mediator of lenvatinib resistance (83). Co-treatment with a CDK2 inhibitor induced senescence and reprogrammed resistant cells into a non-proliferative state. At the epigenetic level, Sheng et al. [2025] and Gu et al. [2025] targeted lysine acetyltransferase 5 (KAT5) and cullin 4B (CUL4B), respectively (62,91). These approaches reprogram gene expression and restore differentiation, thereby reversing resistance. Deeper mechanistic insight was provided by Hou et al. [2025], who identified NOP2/Sun RNA methyltransferase 2 (NSUN2)-mediated RNA modification as a driver of multidrug resistance, paving the way for the development of next-generation resistance-reversal agents (69).

Beyond conventional kinases and signalling pathways, unexpected therapeutic targets have also emerged. Bandini et al. [2025] explored melanocortin-4 receptor (MC4R) antagonists, introducing neuroendocrine receptors as a novel class of anticancer targets (49). Rodrigues et al. [2024] reported that silencing protein inhibitor of activated STAT 2β (PIAS2β) selectively induces mitotic catastrophe, a distinct cytotoxic mechanism potentially applicable to various anaplastic tumors (88). These discoveries suggest that the therapeutic landscape of ATC is far broader and more diverse than previously imagined.

Clinical translation and therapeutic applications

Clinical studies have validated the translational pathway from bench to bedside, whilst also highlighting the complexity of precision therapy (Table 3). The combination of dabrafenib and trametinib has undergone a transformation from exploratory treatment to established standard of care. The ROAR basket trial (Subbiah et al., 2022) reported an objective response rate (ORR) of 56% and a mOS of 14.5 months, solidifying its clinical position (5). Subsequent validation studies across different regions confirmed the generalisability of efficacy. Taiwanese cohort (Chang et al., 2022) demonstrated an impressive ORR of 81.8% (116). And the emerging regimen of encorafenib plus binimetinib showed promising results in a Japanese phase II study, with an ORR of 80% and a 12-month progression-free survival (PFS) rate of 78.8% in five BRAF-mutant ATC patients (112).

In contrast, targeting VEGFR has shown certain limitations and requires optimisation. The phase II trial by Wirth et al. [2021] reported a disappointing ORR of only 2.9% (124). However, subsequent studies suggested nuanced applications. A multicentre study by Mikoshiba et al. [2025] revealed limited efficacy but good tolerability; notably, the low-dose group showed slightly better PFS, indicating the potential value of dose individualisation (110). Sparano et al. [2021] found that patients with mixed histology might derive benefit (123). And Yamazaki et al. [2020] identified a significant correlation between FGFR4 expression and PFS, suggesting its potential as a predictive biomarker for lenvatinib response (34).

Gene fusion targeting has demonstrated the power of precision therapy. Although rearranged during transfection (RET) and neurotrophic tyrosine receptor kinase (NTRK) fusions are rare, targeted therapy has yielded remarkable results. For instance, a patient with coiled-coil domain containing 6 (CCDC6)-RET fusion achieved durable remission exceeding 19 months with selpercatinib treatment (118,160). However, acquired resistance remains a major challenge. A recent case by Marczyk et al. [2025] involving NTRK fusion emphasised the inevitability of resistance, even to highly effective targeted agents (109). To overcome the limitations of monotherapy, combination approaches are being explored. Zheng et al. [2023] reported encouraging results using anlotinib combined with chemotherapy in newly diagnosed advanced ATC, achieving an ORR of 60%, a disease control rate (DCR) of 88%, and a median PFS of 25.1 weeks (114).

In summary, targeted therapy for ATC is transitioning from a “target-driven” to a “mechanism-driven” paradigm. By integrating multi-dimensional strategies and implementing precision medicine based on molecular subtyping, targeted therapy is reshaping the therapeutic landscape of ATC. These strategies include tumor-intrinsic targeting, TME remodelling, and resistance reversal.

Immunotherapy strategies and advances

Immune landscape and preclinical discoveries

In recent years, preclinical studies of ATC immunotherapy have established a systematic framework, focusing on converting “immune-cold” tumors into “immune-hot” ones through target discovery and combination strategy optimisation (Table 4). Although the PD-1/PD-L1 axis remains the cornerstone of immunotherapy, ATC frequently exhibits primary or acquired resistance. To overcome the limitations of conventional immune checkpoint blockade, several studies have identified novel immune checkpoints independent of the PD-L1 pathway. For instance, Bao et al. [2024] identified high expression of sialic acid binding Ig like lectin 15 (SIGLEC15) in ATC. They demonstrated that antibody-mediated blockade of SIGLEC15 enhanced T cell and natural killer (NK) cell functions, suggesting a potential therapeutic alternative for patients resistant to PD-1 blockade (15). Additionally, Liu et al. [2024] revealed a key role of the complement system in immune evasion by ATC. They showed that activation of complement C5AR1 promotes immunosuppression through the TLR1/2 and MyD88 signaling axis, highlighting a critical interplay between innate and adaptive immunity (23).

Recognising the limitations of checkpoint blockade alone, research has shifted toward comprehensive remodelling of the TME. A breakthrough by Han et al. [2024] showed that famitinib not only inhibits angiogenesis but, when combined with anti-PD-1 therapy, also promotes the formation of TLSs and the enrichment of CXCL13⁺ T cells (13). This may explain the heightened sensitivity of some ATC tumors to immunotherapy—TLSs serve as local immune hubs capable of sustaining tumor-specific T cell responses. Meanwhile, multiple studies have explored strategies to induce immunogenic cell death (ICD): Xu et al. [2023] demonstrated that paclitaxel combined with TLR4 knockout induces ICD (128). And Hegedűs et al. [2020] used histone deacetylase inhibitors to upregulate PD-L1 expression, converting tumors from an “immune-invisible” to an “immune-recognisable” state (132).

In parallel with TME remodelling, researchers have developed various strategies for precise drug delivery and enhancement of effector cell activity. Zhang et al. [2023] engineered an ICAM1-antibody-drug conjugate (ADC) that not only achieved targeted cytotoxicity but also provided diagnostic functionality (129). Furthermore, Gray et al. [2020] showed that PD-1 blockade can augment the efficacy of ICAM1-CAR-T cells, underscoring the synergy between passive and active immunotherapies (134). These combinatorial successes have spurred the exploration of more innovative approaches. One strategy redirects pre-existing antiviral immunity to eliminate tumors using a preS1 antigen (Zhang et al., 2025) (127). Another employs a triple-combination of oncolytic viruses to convert tumor cell death into an immunostimulatory event (Crespo-Rodriguez et al., 2020) (133).

Beyond these advances, investigations into the molecular mechanisms of immune evasion have provided insights into overcoming resistance. Wang et al. [2021] first identified a long non-coding RNA urothelial carcinoma-associated 1 (lncRNA UCA1)-microRNA-148a (miR-148a)-PD-L1 regulatory axis, where UCA1 competitively binds miR-148a, releasing its inhibitory effect on PD-L1 (130). Zou et al. [2025], through transcriptomic profiling, revealed a complex network linking immune evasion, inflammation, and metastasis—suggesting that multi-targeted interventions are needed (126).

Clinical translation and therapeutic applications

Clinical studies have validated the pathway from basic research to clinical application, whilst also overturning the traditional belief that “ATC is universally resistant to immunotherapy” (Table 5). Biomarkers have redefined the patient population suitable for immunotherapy. For a long time, ATC was considered a “no-go zone” for immunotherapy, but breakthrough case reports by Chai et al. [2025] and Nabhan et al. [2021] have changed this perception. Both studies described cases of patients with high PD-L1 expression (≥95%) who achieved sustained complete remission with tislelizumab and pembrolizumab, respectively (135,139). This stands in stark contrast to the 16% ORR reported by Hatashima et al. [2022] in unselected patients, highlighting the critical role of biomarker screening (21).

Given the limited efficacy of monotherapy for ATC in immunotherapy, researchers have explored various combination regimens. Sehgal et al. [2024] demonstrated that dual immune checkpoint inhibition (nivolumab plus ipilimumab) increased the ORR to 30%, confirming the synergistic effects of targeting different immune checkpoints (136). However, not all combinations were effective. For example, Lee et al. [2022] reported that a triplet regimen of dual immunotherapy and radiotherapy yielded suboptimal results. This outcome indicates that rational, mechanism-based design is essential, and simple combination is insufficient (137).

For patients resistant to PD-1 blockade, Kroloff et al. [2022] used a bispecific antibody (LAG-3/PD-L1) called FS118, achieving 3 years of sustained remission, validating the potential value of new targets discovered in preclinical studies (138). This successful case provides confidence for clinical trials targeting novel immune checkpoint molecules such as SIGLEC15 and C5AR1. In summary, immunotherapy for ATC is transitioning from empirical trials to a mechanism-driven approach. By gaining a deeper understanding of TME characteristics, developing novel targets, and optimising combination strategies, immunotherapy holds the potential to offer survival benefits for a greater number of ATC patients.

Combination therapy strategies

Establishment and progress of standard combination regimens

Due to the limitations of single-agent therapies, targeted and immunotherapy combination strategies are becoming a new paradigm for ATC treatment, overcoming treatment bottlenecks through multi-mechanism synergy (Table 6). The advantages of combination therapy have been well validated in patients with BRAF V600E mutations. Although the traditional dabrafenib/trametinib dual regimen has significantly improved prognosis, the addition of ICIs further enhances efficacy. A large retrospective study by Hamidi et al. [2024] with 71 patients confirmed that the combination of dabrafenib/trametinib and pembrolizumab significantly outperformed the dual regimen alone, with median OS extended from 9 to 17 months and median PFS extended from 4 to 11 months (17). Notably, in the neoadjuvant treatment group, the median OS reached an impressive 63 months, setting a new survival record for ATC. This groundbreaking progress has been validated by multiple studies: Cabanillas et al. [2024] in a phase II trial reported that atezolizumab combined with personalised targeted therapy led to a median OS of 19 months, with the BRAF-mutant subgroup showing the most significant benefit (18).

For patients without BRAF mutations, anti-angiogenesis TKIs combined with ICIs have become an important treatment approach. Dierks et al. [2021] reported that lenvatinib combined with pembrolizumab achieved complete remission in 66% of six ATC patients, with some patients achieving PFS for over 2 years (151). This synergistic effect, “1+1>2”, has been validated in multiple studies. Song et al. [2024] reported outcomes in 18 advanced ATC patients treated with TKIs (lenvatinib or anlotinib) plus PD-1 inhibitors (146). The ORR was 61.1%, with a median OS of 14 months. Importantly, 38.9% of patients underwent surgical resection. A prospective study by Zhang et al. [2025] further confirmed that anlotinib combined with sintilimab led to significant tumor shrinkage in most patients, with improvements in both lung metastases and cervical lymph node lesions (141).

With the continuous progress in precision molecular profiling, combination therapy is also transforming clinical practice. Wu et al. [2024] conducted a retrospective analysis of 55 ATC patients, with treatment based on molecular characteristics selecting combinations of dabrafenib/trametinib, anlotinib, or PD-1 inhibitors, achieving a 1-year survival rate of up to 73% (145). Specific mutation types are increasingly guiding targeted therapy. Gui et al. [2023] first reported an ATC patient with dual NRAS Q61R and BRAF D594N mutations who achieved complete pathological remission following treatment with dabrafenib, trametinib, and sintilimab (149). This case highlights a mutation-specific therapeutic strategy. Ma et al. [2022] confirmed that RET-positive patients who received cabozantinib combined with nivolumab survived for over 30 months (155). Notably, patients traditionally considered “refractory” also seem to benefit from combination therapy. Jiang et al. [2025] reported that a PD-1 negative squamous cell variant of ATC still achieved disease control with a combination of tislelizumab and anlotinib (140). Gui et al. [2021] and Zheng et al. [2021] respectively confirmed that PD-L1 high-expressing patients without identifiable targetable mutations achieved remission for over 11–18 months with the combination of sintilimab plus anlotinib or camrelizumab plus apatinib (152,159).

Neoadjuvant combination therapy creates surgical opportunities

Neoadjuvant combination therapy is rewriting the surgical indications for ATC, transforming it from “unresectable” to “resectable”. Maurer et al. [2023] successfully provided surgical opportunities for three patients with stage IVB/IVC disease through individualised short-term neoadjuvant treatment (dabrafenib/trametinib or pembrolizumab/lenvatinib), with postoperative specimens showing a high proportion of tumor necrosis in some cases (150). Yang et al. [2023] reported that BRAF wild-type patients who received neoadjuvant treatment with famitinib/camrelizumab successfully achieved R0 resection (157). A retrospective analysis by Xu et al. [2025] further confirmed that neoadjuvant strategies, including targeted therapy ± immunotherapy ± chemotherapy, could improve resectability and prognosis (144).

Exploration of innovative combination models

Local and systemic treatments show an increasing trend of integration. For example, Tan et al. [2024] applied QUAD-shot low-dose radiotherapy combined with pembrolizumab (± lenvatinib) in five patients. The ORR reached 80%, including two complete remissions, and enhanced T-cell activation was observed (147). A case series by Xing et al. [2025] showed that multimodal radiotherapy combined with anlotinib/toripalimab achieved long-lasting remission in patients with multiple organ metastases (142). In a phase II clinical trial, Zhao et al. [2022] found that apatinib induced pyroptosis. When combined with melittin, it synergistically enhanced antitumor effects via the gasdermin D/caspase dual-axis pathway (158). This mechanism-based combination design provides insights into future research directions.

Clinical trade-offs between efficacy and safety

Whilst targeted therapy and immunotherapy can alleviate disease to some extent, the drug-related toxicities remain a challenging issue. Hamidi et al. [2024] reported that 32.4% of patients experienced immune-related adverse events, such as hepatitis or colitis, which required treatment interruptions or management with corticosteroids (17). Similarly, Kulkarni et al. [2021] reported that BRAF V600E-positive patients initially achieved significant relief with dabrafenib/trametinib but were forced to reduce the dosage due to intolerance, ultimately leading to rapid disease progression (153). A similar dilemma was observed in the case series by Shih et al. [2022], where two of four patients required treatment adjustments due to severe rashes and liver dysfunction (156). These clinical experiences underscore the importance of establishing a robust toxicity monitoring system and developing individualised dose adjustment strategies to ensure that patients can continue to benefit from combination therapy.

In summary, combinations of targeted and immunotherapy are transforming ATC from an “incurable” to a “controllable” or even “curable” disease. These regimens act through multiple synergistic mechanisms, such as reversing immune suppression, normalizing tumor vasculature, and enhancing tumor antigen presentation.

Discussion

This study systematically analyses recent advances in ATC TME research and its applications in targeted and immunotherapy. Our findings reveal that the TME is both a key driver of ATC malignancy and a core target for overcoming therapeutic bottlenecks. Our comprehensive analysis indicates that the shift from “tumor cell-centric” to “TME-directed” therapeutic strategies is fundamentally changing the clinical management model of ATC.

ATC’s TME exhibits the paradoxical feature of “immune activation and immune suppression coexisting”, providing a fresh perspective for precision treatment. Previous studies have demonstrated that compared to DTC, ATC contains a higher enrichment of TLS and CXCL13⁺ T cells, which may explain why certain ATC patients show unexpectedly high response rates to immunotherapy (13). Recent studies suggest that the extent of TLS and CXCL13⁺ T cell enrichment could serve as key predictors for immunotherapy responses (161-163). Research by Helmink et al. [2020] in melanoma and renal cell carcinoma confirmed that TLS-positive patients exhibited three times higher immune therapy response rates than negative patients (164). This finding is equally applicable to ATC, suggesting that TLS could be an important biomarker for patient selection (165).

However, a major challenge in clinical practice lies in how to accurately assess the TME state. Traditional PD-L1 expression tests, whilst valuable, do not comprehensively reflect the complexity of the TME (166). Zeng et al. [2022] developed the TME score system, which integrates multi-omics data and outperforms single biomarkers [PD-L1, tumor mutational burden (TMB), and microsatellite instability (MSI)] in predicting immunotherapy response in gastric cancer (167). We recommend establishing a similar comprehensive assessment system for ATC, incorporating multiple parameters such as CXCL13 expression, TLS density, and the M2/M1 macrophage ratio.

Our analysis also revealed key mechanisms through which targeted therapy reshapes the TME to create favourable conditions for immunotherapy. BRAF/MEK inhibitors directly kill tumor cells and, more importantly, modulate the TME. They enhance tumor antigen presentation, promote T cell infiltration, and reduce immunosuppressive factors, collectively converting immunologically “cold” tumors into “hot” ones (168). However, the optimal combination for combination therapies remains controversial. In BRAF-mutant patients, although the triple therapy (BRAF/MEK inhibitors plus PD-1 antibody) shows significant efficacy, the 32.4% incidence of severe adverse events cannot be ignored (17). This is consistent with Gutzmer et al. [2020]’s observations in melanoma, suggesting the need for more precise dosing strategies (169). Sequential therapy may be a solution to balance efficacy and toxicity, where targeted therapy remodels the TME before immunotherapy is introduced.

For patients without driver gene mutations, anti-angiogenesis combined with immunotherapy shows promise. Dierks et al. [2021] demonstrated that lenvatinib combined with pembrolizumab achieved a 66% complete remission rate, which is encouraging (151). Fukumura et al. [2018] showed that moderate anti-angiogenic therapy can convert tumor vasculature from “abnormal” to “normalised”, creating a microenvironment favourable for immune cell infiltration (170).

Despite the encouraging data from clinical trials and case reports, real-world clinical treatment still faces several challenges. First is the issue of patient heterogeneity. Most ATC patients are elderly and often have multiple comorbidities, limiting the application of intensive treatments. Maniakas et al. [2020] found that fewer than 40% of ATC patients could receive standard treatments in clinical trials (171). Secondly, the accessibility of molecular testing remains a challenge. Although BRAF mutation testing is relatively common, comprehensive genomic analysis and TME assessment are still difficult to achieve in many healthcare institutions. Third, the issue of medical costs arises. The annual cost of combination therapies may reach several hundred thousand dollars, posing a significant burden on both healthcare systems and patients’ families (172).

This narrative synthesis has inherent constraints. First, we restricted our search to English-language publications, potentially missing relevant studies in other languages. Second, although we analyzed 129 studies, the predominance of small, single-arm studies and heterogeneous case series limits causal inference and increases susceptibility to selection and publication biases. Third, we restricted preclinical evidence to in vivo animal models to enhance translational relevance; however, different model systems (xenograft/PDX/syngeneic) variably recapitulate the stromal and immune contexts of human ATC. Fourth, outcome definitions, follow-up durations, and reporting of safety signals were inconsistent across studies, precluding meta-analysis. Finally, access to comprehensive molecular/TME profiling and combination regimens differs widely across settings, which may restrict generalizability. These limitations should temper over-interpretation and motivate prospective, adequately powered, TME-stratified trials with standardized endpoints.

Beyond methodological constraints of this review, the field faces substantial clinical challenges in translating evidence to practice. Current studies demonstrate the value of combined targeted and immunotherapy. BRAF/MEK inhibition has become standard for BRAF-mutant ATC. RET/NTRK inhibitors benefit fusion-positive cases. ICIs with antiangiogenic agents show efficacy across molecular subtypes. However, considerable heterogeneity persists in reported outcomes. Response rates vary widely between Asian and multinational cohorts. Comparative benefits of specific combinations remain unclear. Optimal treatment sequences are undefined. These discrepancies reflect both methodological limitations and real-world barriers. Trial populations often exclude elderly patients with comorbidities, limiting generalizability. Many institutions lack access to comprehensive molecular and TME profiling. Combination therapies impose a substantial financial burden, with annual costs exceeding several hundred thousand dollars. Addressing these gaps requires prospective randomized trials with standardized protocols and uniform patient stratification. Pragmatic implementation research is equally needed to guide real-world clinical decision-making.

Finally, to our knowledge, this study is the first to systematically analyse the progress of animal and clinical research in the field of ATC targeted and immunotherapy from 2020 to 2025. Through in-depth analysis of 129 ATC-related studies, we comprehensively demonstrate the central role of TME in breakthroughs in ATC treatment.

Conclusions

This review demonstrates that the TME is both a key driver of ATC malignancy and a critical therapeutic target. TME-directed strategies combining targeted therapy with immunotherapy are transforming this historically fatal disease into an increasingly manageable condition. TME profiling holds promise for patient stratification. Tumors with TLSs and CXCL13⁺ T cell infiltration show enhanced immunotherapy responses, while M2 macrophage predominance correlates with immunosuppression. However, clinical translation requires prospective validation of these biomarkers alongside established markers such as BRAF mutation status and PD-L1 expression. Standardized assessment protocols and validated cut-off values are essential prerequisites. The optimal sequencing of targeted and immune therapies in BRAF-mutant patients also requires clarification.

Real-world implementation faces substantial barriers. Many institutions lack access to comprehensive TME profiling. Combination therapies impose significant financial burden. Trial populations often exclude elderly patients with comorbidities, limiting generalizability. Advancing TME-guided precision oncology requires integrated efforts spanning biomarker validation, diagnostic standardization, and implementation research. Such coordinated approaches may ultimately enable personalized therapeutic strategies that improve outcomes for ATC patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1882/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1882/prf

Funding: This work was supported by the Startup Fund for Scientific Research at Fujian Medical University (No. 2021QH1222, awarded to F.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1882/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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