Strategies Targeting FGF/FGFR Signaling

The pivotal role of FGF/FGFR signaling in diverse physiological and pathological processes positions it as a promising therapeutic target for a broad spectrum of diseases, including cancer, metabolic disorders, and developmental abnormalities. To address either pathological hyperactivation or functional deficiency of this pathway, a diverse and multi‐level intervention strategy has been developed. These strategies modulate FGF/FGFR signaling through distinct mechanistic modalities, such as blocking signal transduction, inducing receptor degradation, or employing FGF ligand analogs. Collectively, these strategies have demonstrated substantial efficacy in preclinical models and clinical studies (Table 2).

Therapeutic strategy | Category | Drug | Targets | Disease | Clinical stage | References
Strategies targeting the abnormal activation of FGF/FGFR signaling | Non‐selective TKIs | Erdafitinib | FGFR1–4 | Cancers with FGFR mutations | Clinically approved | [369]
Dovitinib (TKI258) | FGFR1–4 | Cancers with FGFR mutations | Phase II (NCT01741116) | [370]
Rogaratinib | FGFR1–4 | Cancers with FGFR mutations | Phase II/III (NCT03410693) | [371]
ARQ 087 (derazantinib) | FGFR1–4 | Cancers with FGFR mutations | Phase I/II (NCT01752920) | [372]
KIN‐3248 | FGFR1–4 | Cancers with FGFR mutations | Phase I (NCT05242822) | [373]
Futibatinib | FGFR1–4 | Cancers with FGFR mutations | Clinically approved | [374]
Selective TKIs | Pemigatinib | FGFR1–3 | Cancers with FGFR mutations | Clinically approved | [375]
AZD4547 | FGFR1–3 | Cancers with FGFR mutations | Phase I/II (NCT02824133) | [376]
Infigratinib | FGFR1–3 | Cancers with FGFR mutations | Clinically approved | [377]
BLU9931 | FGFR4 | Cancers with high FGFR4 expression | Preclinical | [378]
BLU‐554 (fisogatinib) | FGFR4 | HCC | Phase I/II (NCT04194801) | [379]
H3B‐6527 | FGFR4 | HCC | Phase I (NCT02834780) | [380]
Irpagratinib (ABSK‐011) | FGFR4 | HCC | Phase II (NCT07010497) | [381]
RLY‐4008 | FGFR2 | iCCA | Phase I/II (NCT04526106) | [382]
Monoclonal antibody | R3Mab | FGFR3 | Tumor | Phase I/II (NCT02401542) | [383]
U3‐1784 | FGFR4 | HCC | Phase I (NCT02690350) | [384]
Bemarituzumab (FPA144) | FGFR2b | Tumor | Phase I (NCT05913115) | [385]
Antibody–drug conjugate | LY3076226 | FGFR3 | Tumor | Phase I (NCT02529553) | [386]
Aprutumab ixadotin (BAY 1187982) | FGFR2 | Tumor | Phase I (NCT02368951) | [387]
Ligand trap | FP‐1039 (GSK3052230) | FGF ligands | Tumor | Phase I (NCT01868022) | [388]
Aptamer | RSc6/RSc37 (RNA aptamers) | FGFR3 | Skeletal development regulation | Preclinical | [389]
RBM‐007 (anti‐FGF2 aptamer) | FGF2 | Wet AMD, ACH | Phase II (NCT04640272) | [390]
TD0 (DNA aptamer) | FGFR1 | Stem cell culture, tissue regeneration | Preclinical | [391]
 | Cell therapy | FGFR4‐CAR T cells | FGFR4 | RMS, HCC, CCA | Preclinical | [357]
FGFR4/CD276 bispecific CART | FGFR4/CD276 (B7‐H3) | RMS | Preclinical | [392]
Gene therapy | AAV9FGFR2shRNA | Mutant FGFR2P253R | Apert syndrome | Preclinical | [393]
CRISPR/Cas9 correction | Mutant FGFR3G374R | Dwarfism | Preclinical | [394]
Strategies targeting the inactivation of FGF/FGFR signaling function | FGF analogs | LY2405319 (LUM‐201) | FGF21 | T2DM, obesity, NASH | Preclinical | [329]
Repifermin (rFGF10) | FGF10 | Oral and intestinal mucositis | Phase II (PMID: 11896977) | [395]
NGM282 (aldafermin) | FGF19 | NASH, PBC | Phase II (NCT02443116) | [396]
Sprifermin (rhFGF18) | FGF18 | OA | Phase II (NCT01689337) | [397]
LY2405319 (LUM‐201) | FGF21 | T2DM, obesity, NASH | Preclinical | [329]
Burosumab | FGF23 | XLH, TIO, ARHR1 | Phase II (NCT02163577) | [398]
M70 | FGF19 variant | NASH, PBC | Preclinical | [399]
Efruxifermin (AKR‐001) | FGF21 | NASH | Phase II (NCT04767529) | [400]
Pegbelfermin (BMS‐986036) | FGF21 | NASH | Phase II (NCT03486912) | [401]
Gene therapy | NV1FGF | FGF1 | CLI | Phase III (NCT00566657) | [402]
Ad5FGF‐4 | FGF4 | IHD | Phase II/III (NCT00346437) | [403]
AAV FGF18 | FGF18 | ACH | Preclinical | [404]

Strategies Targeting the Abnormal Activation of FGF/FGFR Signaling

Aberrant activation of the FGF/FGFR signaling contributes to the pathogenesis of multiple disorders, including abnormal bone development, metabolic and endocrine diseases, as well as diverse malignancies. Currently, several targeted therapeutic strategies have been developed to inhibit this hyperactivated axis, including small‐molecule tyrosine kinase inhibitors (TKIs), proteolysis‐targeting chimeras (PROTACs), mAbs and antibody‐derived therapeutics, chimeric antigen receptor T‐cell (CAR‐T) therapy, and gene interference approaches.

Small‐Molecule TKIs

Small‐molecule TKIs currently represent the most extensively developed class of FGFR‐targeted agents in clinical practice. These agents competitively inhibit FGFR kinase activity by occupying the ATP‐binding pocket, thereby suppressing downstream signaling cascades [405, 406]. Pan‐FGFR inhibitors exhibit differential inhibitory potency against FGFR1–4 and are indicated for tumors harboring diverse FGFR genomic alterations, including gene amplifications, mutations, and fusions.

Erdafitinib, an oral small‐molecule FGFR TKI, that has been approved for patients with advanced urothelial carcinoma carrying FGFR2 or FGFR3 alterations. In the Phase II RAGNAR trial, erdafitinib achieved an objective response rate of approximately 30% across a spectrum of FGFR‐altered solid tumors [369]. Futibatinib is an irreversible, covalent FGFR inhibitor that achieves durable target suppression through forming a stable bond with a conserved cysteine residue within the FGFR kinase domain. It has been approved for patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusion or rearrangement. Clinical evidence also shows its therapeutic activity in other solid tumors driven by oncogenic FGFR alterations [374, 407, 408]. Pemigatinib is a selective FGFR1‐3 inhibitor that demonstrates clinically meaningful efficacy in patients with advanced cholangiocarcinoma carrying FGFR2 fusions or other rearrangements and has received approval for this indication [375], with its indications gradually expanding to additional FGFR‐altered malignancies, including urothelial carcinoma [409]. AZD4547 is an ATP‐competitive inhibitor that has shown potent activity in preclinical studies [410]. However, its clinical translation has been limited by modest efficacy and tolerability challenges in human trials. It has been evaluated in multiple clinical studies, including in patients with FGFR2‐amplified gastric cancer [411], endocrine‐resistant breast cancer [412], and LSCC [413]. Other pan‐FGFR inhibitors under clinical investigation include dovitinib (TKI258) [414], rogaratinib (with patient selection based on FGFR1/3 mRNA expression) [371], infigratinib (BGJ398) [377], ARQ087 [415], and the next‐generation irreversible inhibitor KIN‐3248 [416].

FGFR4 plays a specific oncogenic role in FGF19‐driven HCC [417, 418], whereas pan‐FGFR inhibitors targeting FGFR1–4 frequently induce dose‐limiting toxicities, including hyperphosphatemia. Therefore, the development of highly selective FGFR4 inhibitors has emerged as a major therapeutic priority. BLU9931, an early‐generation, covalent FGFR4 inhibitor, has not advanced to clinical approval but remains a foundational chemical tool that provided critical proof‐of‐concept and high‐resolution structural insights for subsequent FGFR4‐targeted drug design [378]. Fisogatinib (BLU‐554) is an irreversible FGFR4 inhibitor rationally engineered from BLU9931, and its high selectivity for FGFR4 is achieved through covalent engagement of Cys552 within the FGFR4 kinase domain [419]. Preclinical studies demonstrate that BLU‐554 induces potent cytotoxicity and cellular senescence in FGFR4‐activated cell lines [420]. Additionally, H3B‐6527 represents another highly selective FGFR4 inhibitor [421], and it completed a Phase I clinical trial demonstrating favorable tolerability and preliminary antitumor activity in patients with HCC harboring either FGF19 overexpression or activating FGFR4 mutations [380]. ABSK‐011 (irpagratinib), also an irreversible FGFR4 inhibitor, has progressed to late‐stage clinical trials. Compared with fisogatinib, irpagratinib achieves more sustained target inhibition through its unique covalent bonding mechanism and has shown preliminary efficacy in patients with FGF19‐overexpressing advanced HCC [422].

With the widespread clinical application of FGFR inhibitors, acquired resistance has gradually emerged as a principal limitation to durable therapeutic response. Several resistance mechanisms have been identified to date. One well‐documented category involves secondary kinase domain mutations, such as the FGFR2 gatekeeper mutation (V565I) and multiple‐site mutations, which either sterically hinder inhibitor binding to the ATP‐binding pocket or stabilize the active kinase conformation, thereby reducing drug affinity [423, 424]. Alternatively, tumor cells may maintain signaling flux through downstream RAS–RAF–MEK–ERK and PI3K–AKT–mTOR pathways via activation of bypass signaling routes, including EGFR, HER2/HER3, MET, and STAT3. This alternative signaling enables tumor cells to evade FGFR inhibitor‐mediated suppression [294, 425, 426]. Additionally, prolonged exposure to FGFR inhibitors can also promote EMT, driving some tumor cells to acquire resistance [427]. To address these challenges, the next generation of FGFR inhibitors have been rationally designed to retain potency against a broader spectrum of genetic aberrations and clinically observed resistance variants. RLY‐4008 (lirafugratinib) is a first‐in‐class, highly selective, irreversible FGFR2 inhibitor approved for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions, rearrangements, or activating mutations. It maintains robust activity against gatekeeper and other resistance‐conferring FGFR2 mutations, including V565I, and demonstrates clinically meaningful efficacy in biomarker‐selected patients, with a manageable safety profile dominated by on‐target hyperphosphatemia [428]. KIN‐3248 is another irreversible pan‐FGFR inhibitor engineered to overcome kinase domain mutation‐mediated resistance across FGFR2 and FGFR3, and preclinical and Phase I data support its activity in resistant models and early clinical signals of antitumor efficacy, though its development was terminated early for commercial reasons [416]. For context‐specific resistance mechanisms, such as STAT3 activation and EMT driven by the FGFR1 V561M mutation, rational combination strategies (e.g., FGFR plus STAT3 or MEK inhibition) are under active clinical investigation as an effective strategy to overcome resistance [294].

Protein Degradation‐Targeting Chimeras

PROTACs represent an innovative therapeutic modality that induces selective degradation of target proteins through recruitment to E3 ubiquitin ligases, leading to polyubiquitination and subsequent proteasomal destruction [429, 430]. At the core of this strategy are heterobifunctional molecules, comprising a target‐binding ligand, a linker, and an E3 ligase–binding moiety, that physically bridge the target protein and the ubiquitination machinery. To date, PROTACs directed against FGFR1 [431, 432], FGFR2 [433, 434], and FGFR3 [435] have demonstrated robust antitumor activity in preclinical studies by achieving sustained target depletion, offering a mechanistically distinct approach to circumvent resistance mechanisms associated with conventional FGFR‐TKIs. Furthermore, emerging innovations include photocontrolled PROTACs, engineered to undergo structural activation only upon exposure to specific wavelengths of light (e.g., ultraviolet or near‐infrared), enabling precise spatiotemporal control of protein degradation. This strategy significantly reduces off‐target effects and enhances on‐target specificity, thereby improving the therapeutic index [436].

mAbs and Their Derivatives

mAbs exert their therapeutic effects through a mechanism fundamentally distinct from that of small‐molecule TKIs. These agents bind with high affinity and specificity to the extracellular domain of FGFR receptors or to FGF ligands, thereby sterically inhibiting ligand–receptor engagement and downstream signal initiation [55, 437]. Unlike TKIs, mAbs do not interfere with intracellular kinase activity; instead, they act extracellularly to prevent pathway activation at its origin. This mechanism confers several pharmacological advantages, including prolonged serum half‐life, minimal off‐target kinase‐related toxicities (e.g., hyperphosphatemia, retinal pigment epithelial detachment), and reduced potential for on‐target resistance mutations in the kinase domain. Consequently, they represent a clinically viable therapeutic strategy for malignancies and skeletal disorders driven by dysregulated FGF/FGFR signaling.

Currently, mAb therapies targeting FGFR receptors have demonstrated substantial antitumor potential in both preclinical and clinical trials. Bemarituzumab is a humanized immunoglobulin G 1 (IgG1) mAb that selectively targets the FGFR2b isoform, and its Fc segment has been modified via glycoengineering to enhance antibody‐dependent cell‐mediated cytotoxicity (ADCC). In the first‐line treatment of patients with HER2‐negative advanced gastric or gastroesophageal junction adenocarcinoma exhibiting FGFR2b protein overexpression, bemarituzumab significantly improved progression‐free survival and overall survival when combined with the mFOLFOX6 chemotherapy regimen [385, 438]. This clinical success not only established FGFR2b overexpression as a clinically validated predictive biomarker but also accelerated the development of AI‐based pathological screening technologies [439, 440]. Furthermore, U3‐1784 is a humanized anti‐FGFR4 mAb engineered with reduced binding affinity to preserve BA homeostasis and mitigate hepatotoxic risk, a key safety consideration given FGFR4's physiological role in BA regulation [441]. Additional FGFR‐targeted antibodies under investigation include antagonistic anti‐FGFR1 antibodies [442], selective anti‐FGFR2c antibodies [443], and anti‐FGFR3 antibodies developed either as standalone therapeutics or as payloads for antibody–drug conjugates (ADCs) [444]. Notably, the R3Mab antibody directed against FGFR3 blocks ligand binding and induces ADCC, demonstrating potent antitumor activity against bladder cancer and multiple myeloma [277].

An alternative approach to inhibit aberrant activation of the FGF/FGFR signaling is ligand neutralization, specifically targeting pathologically elevated circulating FGF ligands. For example, although neutralizing antibodies targeting FGF19 can suppress tumor growth, they are often associated with severe metabolic disorders, such as BA synthesis imbalance, intestine malabsorption, and diarrhea [445]. To mitigate these on‐target metabolic adverse effects while preserving the physiological metabolic function of FGF19, epitope‐selective antibodies have been engineered to bind the N‐terminal domain of FGF19. Such antibodies potently suppress HCC proliferation without perturbing systemic BA homeostasis, thereby achieving a favorable therapeutic index [446].

Ligand traps represent a decoy‐based therapeutic strategy that sequesters extracellular FGF ligands to prevent receptor activation. These engineered proteins typically comprise the soluble extracellular ligand‐binding domain of an FGFR isoform fused to a human IgG1 Fc domain, conferring high avidity for cognate ligands and extending serum half‐life via FcRn‐mediated recycling [447]. By competitively binding free ligands in circulation, ligand traps sterically hinder formation of the functional FGF–HSPG–FGFR ternary complex, thereby abrogating downstream signaling. FP‐1039 (GSK3052230) is a clinical‐stage ligand trap consisting of the FGFR1c extracellular domain fused to an IgG1 Fc fragment; it potently neutralizes multiple FGFR1‐preferring ligands, including FGF2, FGF4, and FGF8, with high affinity. FP‐1039 has demonstrated antitumor activity in malignant pleural mesothelioma (MPM), both as monotherapy and in combination with pemetrexed–cisplatin chemotherapy, and has advanced to Phase II clinical evaluation [448, 449]. Complementary to ligand traps, small‐molecule inhibitors designed to mimic the antiangiogenic domain of thrombospondin‐1 (TSP‐1) have been developed to target the heparin‐binding domain of FGF2. By occupying this site, these compounds disrupt FGF2 dimerization, impair HSPG co‐receptor engagement, and inhibit assembly of the FGF2–HSPG–FGFR1 signaling complex, resulting in potent suppression of FGF2‐driven angiogenesis [450, 451].

At the level of precise killing, ADCs combine the targeting ability of antibodies with highly effective cytotoxic payloads, enabling the specific eradication of tumor cells expressing the relevant receptors. Aprutumab ixadotin (BAY 1187982), an ADC targeting FGFR2, has completed its first‐in‐human Phase I study in patients with advanced solid tumors [387]. LY3076226, an FGFR3‐targeting ADC, has entered early‐stage clinical investigation and demonstrates robust pro‐apoptotic activity in inducing apoptosis in FGFR3‐driven malignancies [444]. Furthermore, ADCs targeting FGFR4 are also under investigation for indications such as RMS and HCC, where FGFR4 dysregulation, driven by FGF19 overexpression or activating mutations, presents a compelling therapeutic vulnerability. Although most FGFR4‐targeted ADC programs remain in preclinical or early clinical stage, their strategy of specifically delivering cytotoxic agents offers a promising avenue to address the limited efficacy and on‐target toxicities associated with conventional FGFR4 inhibitors [452].

In diseases such as XLH and TIO, pathologically elevated circulating FGF23 is the central mediator of renal phosphate wasting and consequent hypophosphatemia. To counteract this mechanism, fully human mAbs targeting FGF23 have been developed to selectively neutralize excess FGF23 in circulation. Burosumab, a human IgG1 mAb, binds the FGF23 N‐terminal domain, preventing its interaction with the FGFR–α‐Klotho receptor complex. It consistently elevates serum phosphate concentrations, improves rickets/osteomalacia severity, and enhances functional outcomes, including mobility, growth velocity in children, and pain scores, in both pediatric and adult XLH patients [453, 454]. On the basis of robust clinical evidence, burosumab has received approval for XLH and, subsequently, for TIO [455]. Complementary to antibody‐based neutralization, Fc fusion proteins comprising the C‐terminal fragment of FGF23 (e.g., FP‐1022) have been engineered as decoy receptors. These agents competitively inhibit FGF23 binding to FGFR–α‐Klotho without globally suppressing FGF23 signaling, thereby preserving its physiological roles in iron metabolism and cardiac function [456]. Concurrently, small‐molecule inhibitors of FGF23 signaling axis are emerging from computational screening and structural simulation efforts. These compounds provide new research tools and potential therapeutic options for pharmacological modulation of the FGF23 pathway [457, 458].

CAR‐T Cell Therapy

CAR‐T therapy involves the ex vivo genetic engineering of autologous T lymphocytes to express surface receptors that confer high‐affinity, antigen‐specific recognition of tumor‐associated surface markers [357]. FGFR4, owing to its relatively restricted and elevated expression in certain solid tumors, has emerged as an attractive target for CAR‐T therapies. Preclinical studies demonstrate that FGFR4‐targeting CAR‐T cells mediate robust cytolytic activity against FGFR4‐positive tumor cells in vitro and induce potent antitumor efficacy in immunocompetent and xenograft RMS models, significantly suppressing tumor growth and promoting near‐complete eradication of established lesions [357, 459].

To mitigate two principal limitations of CAR‐T therapy in solid tumors, antigen heterogeneity‐driven immune escape and on‐target, off‐tumor toxicity, researchers have developed dual‐targeting CAR‐T constructs and inducible safety switch systems. For example, dual‐target CAR‐T cells that recognize both FGFR4 and CD276 (B7‐H3) have been engineered to broaden tumor antigen coverage and reduce the likelihood of immune escape attributable to clonal loss or downregulation of either target antigen [392]. Complementing this approach, inducible caspase‐9 (iCasp9) suicide gene systems have been integrated into FGFR4‐directed CAR‐T cells; administration of the small‐molecule dimerizer drug rimiducid triggers rapid, dose‐dependent apoptosis of >90% of engineered T cells within hours, providing a robust, clinically validated safety mechanism to abrogate severe adverse events [452].

FGFR4‐targeted CAR‐T cells have demonstrated robust antitumor potential in preclinical models of RMS and HCC. However, their clinical translation into solid tumor therapy remains impeded by three well‐characterized barriers, including immunosuppression within the TME, limited cell infiltration efficiency, and the risk of on‐target off‐tumor toxicity. To address these challenges, further optimizing CAR structural design, combining CAR‐T with other immunomodulatory strategies, or implementing precise biomarker screening to identify suitable patient populations will be essential to advance FGFR4‐directed CAR‐T therapy toward clinical utility in solid tumors.

Gene Interference Therapy

Adeno‐associated virus (AAV) vectors constitute a leading platform for in vivo gene delivery [394]. In the context of FGFR‐related monogenic disorders, AAV‐mediated therapeutic strategies have demonstrated robust proof‐of‐concept in multiple animal models. Specifically, for ACH, a skeletal dysplasia caused by gain‐of‐function mutations in FGFR3, therapeutic inhibition via a soluble FGFR3 decoy receptor has emerged as a promising approach. Recifercept, a clinically developed recombinant soluble FGFR3 variant, sequesters pathologically elevated FGF ligands, thereby normalizing aberrant downstream signaling and ameliorating key skeletal phenotypes in murine models of ACH [460]. Meanwhile, the CRISPR/Cas9 technology has been successfully employed to correct the FGFR3 G374R mutation in vivo in murine models of ACH, leading to restoration of the normal skeletal phenotype [461]. In the Apert syndrome model driven by the FGFR2 S252W mutation, RNA interference (RNAi) has been employed to deliver short hairpin RNA (shRNA) targeting the mutant allele, enabling selective suppression of mutant FGFR2 expression and alleviating craniosynostosis symptoms in mouse models [462].

RNAi and antisense oligonucleotides (ASO) can suppress pathway activity by silencing the expression of specific FGFR or FGF gene. Preclinical studies have demonstrated that targeted silencing of the FGFR4 gene using specific siRNAs attenuates downstream oncogenic signaling, including ERK and STAT3 activation, and induces significant reductions in tumor cell proliferation, invasion, and metabolic capacity [314, 463, 464, 465]. Similarly, siRNA‐driven silencing of specific FGF ligands (e.g., FGF2, FGF11) has provided mechanistic insights into their functional roles in tumor initiation and progression [466, 467]. Advances in nanodelivery systems have substantially addressed the limitations of nucleic acid drugs, particularly with respect to in vivo stability and targeted delivery, thereby substantially enhancing their translational viability [468]. Notably, ASO can also be harnessed to modulate RNA splicing processes and have shown application potential in the study of diseases arising from splicing abnormalities [469].

CRISPR/Cas9 gene editing technology allows knockout or correction of specific genes at the genomic level, establishing it as an indispensable platform for functional dissection of the FGF/FGFR signaling and for identifying potential therapeutic targets [470]. For instance, a CRISPR/Cas9 whole‐genome screening in sorafenib‐resistant HCC revealed FGF21 and the Nrf2 pathway as critical determinants of therapeutic resistance [471]. Conversely, a parallel genome‐wide screen in gastric cancer identified multiple kinase targets that modulate the sensitivity of gastric cancer cells to FGFR inhibitors [472]. Despite its considerable promise in preclinical research, off‐target effects and in vivo delivery efficiency remain major obstacles to clinical translation [473]. At present, application of CRISPR/Cas9 in FGF/FGFR signaling research remains exclusively preclinical; nevertheless, its unparalleled capacity to establish causal genotype provides foundational insights into pathway biology and to inform the rational design of next‐generation targeted therapeutics.

Combined Treatment Strategy

The tumor signaling network exhibits profound complexity and robust adaptive redundancy. Consequently, monotherapeutic inhibition of a single node, such as an individual FGFR or downstream effector, frequently yields transient responses and is commonly associated with the emergence of acquired resistance [474]. In HCC, preclinical evidence demonstrates that pharmacologic or genetic inhibition of the FGF19/FGFR4 signaling reprograms the immunosuppressive TME, providing a strong rationale for combining this pathway inhibition with immune checkpoint inhibitors (ICIs) [475]. Additionally, several combination regimens targeting FGFR signaling alongside immune checkpoint blockade have demonstrated encouraging clinical activity in early‐phase trials. For instance, the combination of futibatinib and pembrolizumab (anti‐PD‐1) exhibited preliminary antitumor efficacy in patients with advanced urothelial carcinoma and esophageal cancer, and the safety profile of this regimen has been generally manageable [422, 476]. Concurrently, a Phase I/II trial evaluating erdafitinib combined with cetrelimab (anti‐PD‐1) is ongoing in patients with advanced solid tumors in Japan [477]. In addition, a Phase I study of a selective FGFR4 inhibitor (EVER4010001) in combination with pembrolizumab has completed dose exploration and shown good tolerability [478]. The combination of multi‐target TKI lenvatinib with ICIs has yielded substantial clinical benefits in HCC and other tumor types [479, 480].

For acquired resistance arising from bypass signaling activation, combination strategies integrating FGFR inhibitors with other targeted agents have emerged as a critical therapeutic paradigm. In HCC models, upregulation of EGFR signaling constitutes a key mechanism of resistance to FGFR4 inhibitors. Concurrent pharmacologic blockade of EGFR using agents such as erlotinib or gefitinib not only re‐sensitizes tumor cells to FGFR4 inhibitors but also significantly enhances their antitumor efficacy [425]. In lung adenocarcinoma, FGFR4 potentiates EGFR‐driven oncogenic signaling, and dual pharmacologic inhibition of FGFR4 and EGFR elicits synergistic antitumor effects in preclinical models, including suppression of tumor growth and induction of apoptosis [426]. In hormone receptor‐positive (HR+)/human epidermal growth factor receptor 2‐negative (HER2−) metastatic breast cancer, the triple combination of the pan‐FGFR inhibitor erdafitinib, the endocrine therapy drug fulvestrant, and the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib has advanced to Phase Ib clinical investigation [481]. In addition, given the role of FGFR signaling in regulating extensive alternative splicing of genes, on this basis, combined inhibition of FGFR and splicing regulatory kinase (e.g., serine/arginine protein kinase, SRPK, or CDC2‐like kinase, CLK) has been shown to synergistically induce tumor cell apoptosis; this strategy has shown therapeutic potential in models such as cholangiocarcinoma [482, 483, 484]. Besides, studies have indicated that combining FGFR pathway inhibitors with conventional chemotherapy agents can simultaneously target the rapidly proliferating cell population and its key dependent pathways, achieving more effective tumor suppression. For example, FP‐1039, an FGF ligand trap, is being evaluated in a Phase II clinical trial (NCT02599754) in combination with pemetrexed and cisplatin for unresectable malignant pleural mesothelioma, and this regimen blocks FGF/FGFR signal to inhibit tumor angiogenesis and cell proliferation [449].

Strategies Targeting the Inactivation of FGF/FGFR Signaling Function

Functional impairment or deficient expression of FGF/FGFR signaling also contributes to a range of pathological conditions, including developmental abnormalities and impaired tissue repair. Current therapeutic strategies aimed at restoring pathway activity primarily encompass FGF analogs, aptamers, and gene delivery approaches.

FGF Analogs

Inactivation of FGF/FGFR signaling contributes to the pathogenesis of multiple diseases, such as metabolic dysregulation and impaired tissue repair. To therapeutically restore pathway function, engineered FGF analogs have been developed as a targeted biologics strategy. These analogs are generated by modifying or directly utilizing FGF ligands, particularly endocrine‐type FGFs, and optimizing their pharmacokinetic properties and target specificity through protein engineering. Clinically, FGF analogs are primarily employed for the treatment of metabolic diseases and the promotion of tissue repair [1, 485].

FGF19 plays a crucial physiological role in BA metabolism and the maintenance of glucose homeostasis. However, its mitogenic activity has been confirmed to be closely associated with the risk of HCC [417, 418]. Consequently, retaining the metabolic functions of FGF19 while attenuating its tumorigenic potential represents a central challenge for its clinical application. Leveraging structural biology studies, researchers have systematically dissected the functional domains of FGF19 involved in metabolic regulation versus cell proliferation and have engineered variants that markedly diminish the activation of tumorigenic signaling pathways while preserving the metabolic effects of FGF19 [399, 486]. Notably, these modified FGF19 chimeric molecules have been shown to promote regeneration of fatty liver tissue without inducing tumor formation [487]. FGF19 analogs developed based on this strategy (e.g., NGM282/aldafermin, a 190‐AA peptide, is engineered through domain modification to reduce oncogenic activity while retaining metabolic function) have advanced into clinical trials, primarily for the treatment of NASH and PBC, demonstrating broad promise in the management of metabolic liver diseases [17].

FGF21 is an important endocrine factor involved in regulation of glucose and lipid metabolism. However, its clinical application as a direct injectable therapeutic is limited by its extremely short half‐life in the body and susceptibility to enzymatic degradation [327, 488]. LY2405319 (LUM‐201), a modified FGF21 analog, significantly improves lipid profiles and increases leptin levels in patients with obese Type 2 diabetes mellitus, although its direct glucose‐lowering effect remains relatively modest [329]. Efruxifermin (AKR‐001), an FGF21‐Fc fusion protein developed by Akero Therapeutics, markedly reduces body weight, enhances glycemic control, and has demonstrated potential in reversing liver fibrosis in patients with NASH through high‐affinity binding to the β‐Klotho receptor [489, 490]. PEGylation represents a well‐established protein engineering strategy to enhance the pharmacokinetic and biophysical properties of therapeutic peptides. This approach involves covalent attachment of polyethylene glycol (PEG) molecules to specific sites on FGF21, with consequent prolongation of circulating half‐life and improvement of solubility and stability [491, 492]. Several PEGylated FGF21 analogs are currently under clinical development. Among them, Pegbelfermin (BMS‐986036) has achieved notable lipid‐lowering effects in Phase II clinical trials for patients with severe hypertriglyceridemia [493]. Another common strategy in PEGylation involves fusing FGF21 with the Fc fragment of IgG. This fusion not only exploits the long half‐life conferred by neonatal Fc receptor (FcRn)‐mediated recycling but may also engage ADCC mechanisms. Importantly, these FGF21 analogs exert their metabolic regulatory effects primarily by activating a receptor complex composed of β‐Klotho and FGFR1c, FGFR2c, or FGFR3c [494]. Additional molecular engineering strategies have been developed on this platform. These include fusion of FGF21 with antibody Fc fragment or covalent linkage to scaffold antibodies, with the goal of achieving sustained delivery by leveraging the extended half‐life of antibodies [495, 496]. For example, LY2405319 has been shown to intervene in the progression of NASH by improving hepatic mitochondrial function [497].

Certain paracrine FGFs, owing to their involvement in cell proliferation and tissue nutritional support, can be harnessed for the repair of various tissue injuries. Repifermin, a recombinant human FGF10, has been evaluated in clinical studies for the alleviation of oral mucositis following hematopoietic stem cell transplantation, with supportive evidence also emerging from pilot studies in active ulcerative colitis [498, 499]. Sprifermin (recombinant human FGF18) has been administered intra‐articularly to patients with knee OA, and follow‐up results demonstrated that it slows the loss of cartilage volume and exerts a sustained effect on symptom improvement [500, 501].

Aptamers

Aptamers are synthetic, single‐stranded DNA or RNA molecules that bind to their target molecules with high specificity. DNA aptamers targeting FGFR1, such as TD0, selected using this platform, function as orthosteric agonists, mimicking natural activity and inducing downstream signaling pathway activation [502]. Additionally, RNA aptamers capable of modulating FGFR3 activity have been isolated [389]. The FGF2‐targeting aptamer RBM‐007 is currently under investigation for the treatment of conditions such as age‐related macular degeneration [503]. Owing to their advantages, including facile synthesis, straightforward chemical modification, and low immunogenicity, aptamers hold significant promise for exploring the biological mechanisms of the FGF/FGFR pathway and for developing novel therapeutic strategies.

Gene Delivery Therapy

Gene therapies enable precise regulation of the FGF/FGFR signaling by directly correcting pathogenic gene defects or delivering functional gene products (e.g., specific FGF ligands or receptor variants). These approaches offer advantages such as single‑administration delivery, long‐term sustained expression, and curative potential. As such, gene therapy is emerging as a complementary therapeutic dimension for FGF/FGFR signaling dysregulation‐associated diseases [504, 505].

For instance, NV1FGF‐1 is a vascular gene therapy approach based on the pCOR plasmid vector, administered via a single intramuscular injection. In the field of vascular regeneration, NV1FGF, which delivers the FGF1 gene, has been reported to promote angiogenesis and reduce amputation rates in patients with severe limb ischemia [402, 506]. Clinical trials for intermittent claudication and critical limb ischemia have shown that NV1FGF has the potential to lower amputation risks [506]. In another clinical trial using Ad5FGF‐4, a single delivery of the adenovirus vector to cardiac tissue successfully improved myocardial perfusion and significantly reduced the frequency of angina attacks, demonstrating its therapeutic potential in treating ischemic heart disease [507, 508]. In an acute lung injury model, AAV‑mediated overexpression of the FGF18 gene reduced pulmonary vascular permeability and inhibited NF‐κB pathway activation; the inflammatory response was alleviated as a consequence [509]. In the EC cell line MFE‐280, AAV9‐FGFR2‐shRNA significantly suppresses the soft‐agar colony formation, an effect that reflects its antitumor effect [510].

In conclusion, for diseases driven by dysregulated FGF/FGFR signaling, targeted modulation of this pathway through ligand–receptor binding interference or receptor kinase activity inhibition has emerged as a highly effective therapeutic strategy. With increasing knowledge of the protein structures of FGF/FGFR signaling components, an increasing number of specific FGFR inhibitors and FGF analogs are advancing into clinical trials. Nevertheless, several critical challenges remain. (1) The potential oncogenic effects of FGF analogs warrant considerable attention. For instance, the FGF19 analog aldafermin has not entirely eliminated its pro‐tumorigenic activity and exhibits a marked synergistic effect with MYC, an oncogene commonly implicated in HCC [9]. Thus, balancing the preservation of metabolic benefits with the maximization of safety constitutes a core challenge for the future clinical translation of FGF analogs. (2) Blockade of FGF/FGFR signaling in tumors may provoke bypass signaling, leading to acquired resistance. For example, following prolonged exposure to FGFR inhibitors, some tumor cells acquire resistance through EMT, accompanied by downregulation of FGFR expression and activation of the TGF‐β pathway [477]. Consequently, combined inhibition of FGFR and other key signaling pathways represents a critical strategy to overcome resistance. (3) Precise identification of “beneficiary populations” that are dependent on this pathway is pivotal for the successful implementation of FGF/FGFR targeted therapies. However, standardized clinical detection protocols for FGF/FGFR alterations, such as assays for FGFR gene mutations, amplifications, or fusions, have yet to be established. (4) Given the pleiotropic nature of FGF/FGFR signaling, FGFR inhibitors frequently elicit multiple adverse effects. For example, pemigatinib, an FGFR inhibitor indicated for patients with advanced cholangiocarcinoma harboring FGFR2 fusions or rearrangements, is associated with hyperphosphatemia as a major side effect, which significantly compromises patient tolerance and long‐term medication adherence. Therefore, the pleiotropic effects and safety profiles of FGF/FGFR signaling must be comprehensively evaluated during therapeutic intervention.