Since the 'seed and soil' theory was proposed in
1889 to describe the association between tumor cells and their
surrounding environment (1), a
growing number of researchers have recognized the importance of the
tumor microenvironment (TME) in tumor development (2-4).
As the 'soil' for tumor cell growth, the TME contains nutrients,
regulatory factors, extracellular matrix (ECM), intertwined blood
vessels and diverse stromal and immune cells (5). Interactions between the components
within the TME drive dynamic changes and the alterations of
properties or quantities in certain components, such as decreased T
cell function, increased stromal density and rising levels of
inflammatory cytokines, may affect tumor growth (3). Cancer-associated fibroblasts (CAFs)
are prominent stromal cells within the TME and influence tumor
behavior through multiple complex mechanisms (4). Furthermore, they impede the efficacy
of various tumor therapies, including radiotherapy, chemotherapy
and immunotherapy by enhancing tumor cell stemness and eliciting
immunosuppression (5,6).
CAF characterization primarily relies on morphology
(elongated or stellate shape), biological properties and expression
of canonical biomarkers including α smooth muscle actin (α-SMA),
vimentin, fibroblast activation protein (FAP), platelet-derived
growth factor receptors (PDGFRs), podoplanin, periostin (POSTN),
transgelin (TAGLN), collagen (COL)1A1, COL1A2 and S100A4 (7). However, that these markers are not
universally co-expressed across all CAFs (6). For example, in glioblastoma, the
majority of CAFs co-expressing FAP and PDGFRβ are negative for
α-SMA (6). Multiplex
immunohistochemical analysis in pancreatic cancer has revealed that
only a minor subset of CAFs co-express α-SMA and FAP (8). Markers such as COL1A1, COL1A2,
PDGFRα and vimentin are broadly distributed across diverse CAF
populations, whereas others, including TAGLN, FAP, S100A4, α-SMA
and PDGFRβ, display notable subpopulation-restricted enrichment
(9). This phenomenon has been
conceptualized as CAF heterogeneity, spurring the development of
CAF classification frameworks grounded in transcriptional profiles
or functional characteristics (9).
Among CAF-related markers, FAP shows the strongest
association with other markers (10). It is a type II transmembrane
glycoprotein possessing dual dipeptidyl peptidase and
gelatinase/collagenase activity (10). Notably, evidence has revealed the
protease-independent roles of FAP as a signaling molecule
participating in the regulation of multiple signaling pathways
(10). FAP+ CAFs are a
CAF subset characterized by high FAP expression. The abundance of
FAP+ CAFs increases with advancing tumor stage (11). Given their prominent pro-tumor
functions, FAP+ CAFs have garnered notable attention in
the field of tumor stroma research in recent years (12,13). The cell surface localization of
FAP also allows efficient isolation of FAP+ CAFs via
fluorescence-activated cell sorting, facilitating experimental
characterization and mechanistic investigation (6).
The present review aimed to summarize the cellular
origins, spatial distribution and function of FAP+ CAFs
from a dual perspective as a practical marker delineating the
FAP+ CAF subset and a functional molecule actively
shaping a distinct TME. In addition, the present study aimed to
evaluate diagnostic and therapeutic strategies targeting
FAP+ CAFs and summarize their potential for combination
with existing clinical regimens. The present review aimed to
provide an overall framework outlining the roles of FAP+
CAFs in tumor progression, diagnosis and treatment to promote their
translational application.
CAFs represent a highly heterogeneous cell
population. They originate from diverse precursors including
resident fibroblasts, bone marrow-derived mesenchymal stem cells,
epithelial cells and endothelial cells, macrophages, pericytes and
adipocytes, each of which is driven by distinct activation signals
to acquire a unique CAF-like phenotype (14). There are concomitantly harbored
anti- and pro-tumorigenic and functionally neutral CAFs in tumor
stroma (7,9). Different CAF subtypes exhibit
distinct gene expression profiles, serve dynamic roles in tumor
progression and show differential associations with therapy
responses and clinical outcomes (8). FAP+ CAFs represent one of
the most prevalent CAF populations, therefore, understanding of
their distribution, unique features and the mechanisms driving
their expansion is fundamental for decoding how stromal cells
behave and function in malignant progression and identifying
stage-specific therapeutic vulnerabilities.
From a tissue localization perspective, FAP is
highly expressed in inflammatory lesions and tumor tissue, which
are marked by common pathological features such as tissue
remodeling, angiogenesis and immune cell infiltration (21). By contrast, FAP expression is low
in most normal and adjacent non-neoplastic tissue (22). Analysis of transcriptomic data
from the Human Protein Atlas database reveals that elevated FAP
expression is commonly observed in tumor tissue from patients with
various solid malignancies, including colorectal, gastric, breast,
pancreatic and prostate cancer (23) (Fig.
1). These data suggest that FAP may serve as a potential
biomarker associated with malignant progression.
Similar to the distribution pattern of FAP in
tumors, immunohistochemical staining and spatial transcriptomic
analyses have revealed that FAP+ CAFs are widely
distributed across multiple tumor types, such as breast, lung and
pancreatic cancer, while exhibiting a degree of tissue-specific
spatial preference (9,13,21). In colorectal cancer and
hepatocellular carcinoma, FAP+ CAFs are typically
enriched at the invasive tumor margin, a position that facilitates
their interaction with tumor-infiltrating immune cells such as
macrophages and T cells (24,25). Additionally, FAP+ CAFs
accumulate in perivascular niches or localize near both cancer and
immune cells (26). Collectively,
FAP and FAP+ CAFs exhibit concordant spatial
distribution patterns, with both concentrating in functional niches
associated with metastasis, angiogenesis and immune cell
infiltration (18,21). Thus, the detection of FAP
expression has been widely adopted as a practical method for
inferring the abundance and distribution of FAP+ CAFs in
malignant tumors (21,27,28).
Based on the expression of classic CAF markers, CAF
have been primarily stratified into FAP+ and
α-SMA+ subsets in multiple studies (9,29,30). There is a less prevalent but
consistently observed CAF population co-expressing elevated levels
of both FAP and α-SMA (FAP+ α-SMA+ CAFs)
(31,32). By contrast, certain current
studies have categorized CAFs into three major functional
subpopulations: Myofibroblastic CAFs (myCAFs), inflammatory CAFs
(iCAFs) and antigen-presenting CAFs (apCAFs) based on gene
expression profiles, spatial distribution and functional markers
(33,34). Of note, the CAF subsets defined by
these classification systems share similarities in their molecular
signatures and dominant signaling pathways (Fig. 2).
Recent studies have defined additional novel CAF
population subgroups based on unique gene expression profiles or
functions, including zinc-transporter+,
S100A4+, POSTN+ and CD36+ CAFs
(41,42). Table
I outlines notable CAF subtypes and their key features and
functions associated with tumor growth. Unlike FAP+
CAFs, most newly identified CAF subsets lack highly specific
surface markers, which limits their isolation, functional
characterization and therapeutic targeting (43). FAP defines a CAF cluster that
encompasses both myCAF- and iCAF-like states yet shares a common
molecular tag. Certain newly identified subsets such as mCAFs,
PDPN+ CAFs and POSTN+ CAFs may represent
further subdivisions within this framework based on differences in
functional preference (31,43,44). Therefore, evaluating FAP
expression status is key for future characterization of novel CAF
subsets, which may not only provide an established molecular tag
but also enrich the FAP+ CAF functional map while
avoiding confusion arising from an overly detailed classification
system.
To date, endogenous or pharmacological factors
capable of inhibiting the generation of FAP+ CAFs remain
poorly characterized. Oxytocin suppresses colorectal cancer
progression, in part through the downregulation of FAP expression
(55). Autophagy may be key for
maintaining the FAP+ CAF phenotype within the TME
(56). A deeper understanding of
the mechanisms regulating the generation of FAP+ CAFs
may provide avenues to remodel the stromal microenvironment by
inhibiting the conversion of CAFs into a tumor-promoting state,
thereby informing the development of novel therapeutic
strategies.
Integrated transcriptomic, proteomic and functional
studies have demonstrated the pro-fibrotic capacity of
FAP+ CAFs, enabling efficient synthesis of key ECM
components such as COL and fibronectin (27,39). FAP+ CAFs highly express
the COL11A1 gene, as well as COL1A1 and COL1A2 (encoding type I
COL), all of which are key components of the ECM scaffold (58). Spatial analysis in glioblastoma
has confirmed that COL and fibronectin concentrations in FAP-high
regions exceed those in FAP-low areas by more than threefold
(59). Notably, treatment with
specific FAP inhibitors (FAPIs) decreases the abnormal COL
deposition (60), providing
evidence for the central role of FAP+ CAFs in ECM
synthesis.
Although FAP may not directly regulate all of the
aforementioned pro-tumorigenic or immunosuppressive factors and the
observed co-expression may simply a coincidental signature of
activated CAFs, FAP expression defines a CAF subset that serves a
role in promoting tumor progression (71,79,86). As a critical mediator of
FAP+ CAF-driven tumor promotion, FAP acts as an enzyme
and modulates cytokine and signaling networks, thereby reshaping
the stromal architecture and sustaining crosstalk with tumor cells
and other components within the TME (54,85,87).
The distinct upregulation of FAP in malignant
tissues compared with adjacent normal regions makes FAP an ideal
target for tumor mapping. Concurrently, its key role in promoting
tumor growth underscores its potential as a therapeutic target.
These attributes have spurred development of FAP-directed ligands,
antibodies and FAPIs for both diagnostic and therapeutic
applications (92,93).
For precise tumor localization, FAP-targeting
molecules are conjugated with fluorophores or radionuclides such as
68Ga, 18F and 89Zr, enabling
high-contrast visualization through advanced imaging techniques
including PET and single photon emission CT (92,94). Several FAP-targeted imaging agents
have been developed and show superior diagnostic performance in
preclinical studies across a range of malignancies (95,96). For example,
89Zr-labeled FAP IgG exhibits high uptake in both
subcutaneous tumors and bone metastases, with detectable signals
persisting for up to 72 h post-injection, thereby providing an
extended window for PET/CT imaging (92). Intravenous administration of
68Ga-labeled FAPI is well-tolerated, and its
biodistribution is associated with FAP expression across cancer
types (96). Notably, compared
with ¹8F-fluorodeoxyglucose, 68Ga-FAPI
displays superior tumor-to-background ratios and prolonged
retention across diverse tumor entities. Moreover,
68Ga-FAPI PET/CT shows enhanced sensitivity in detecting
early metastatic lesions (97).
Nevertheless, certain types of benign disease may also exhibit high
FAP expression, leading to non-specific FAPI uptake that may be
misinterpreted as malignant lesions.
For therapeutic applications, FAPIs, antibodies and
peptides are conjugated with therapeutic radionuclides such as
188Re, 177Lu, 225Ac and
90Y (98,99). The physical half-lives of these
radionuclides align with the biological retention times of
FAP-directed molecules in tumors, creating opportunities for
targeted endoradiotherapy (100). For example,
177Lu-labeled FAP-2286 (a FAP-binding peptide) exhibits
favorable tumor uptake and symptom improvement in patients with
rapidly progressing adenocarcinoma (98). In a subset of patients with
advanced thyroid cancer and high FAP expression,
177Lu-labeled FAPI derivatives markedly decrease bone
and lymph node metastases (99).
To date, FAP-targeted radioligand therapy has shown manageable side
effects, including infrequent and reversible hematological
toxicities as well as self-limiting headache and nausea (98). However, whether long-term therapy
may cause adverse effects remains unclear, highlighting the need
for additional data to assess its efficacy and safety.
FAP-targeted phototherapy is a treatment modality
that can selectively eliminate localized lesions upon light
exposure while avoiding systemic radiation exposure. FAP-IR700, a
conjugate of FAP ligands with novel photosensitive dye IR700, can
insert into adjacent lipid bilayers upon near-infrared light
irradiation and causes cell membrane rupture, thereby selectively
eliminating CAFs (101).
In the aforementioned therapeutic approaches, the
structural design of FAP ligands is key as it directly affects
pharmacokinetics, tumor uptake, clearance and therapeutic outcome.
Modifying FAP ligands with chemical groups, such as amide bonds,
can improve their binding affinity to cell surface FAP (93). Structural optimization of
FAP-targeted pharmaceuticals, such as conjugation with
albumin-binding domains or fatty acids, can enhance tumor uptake
and prolong retention and therapeutic effect (99,102). Furthermore, enhancing
selectivity is a key objective to mitigate off-target toxicity by
minimizing the interaction of FAP-targeted drugs and normal cells
with low FAP expression.
FAP-CAR T cells drive a beneficial remodeling of
TME through the dual mechanism of FAP+ CAF depletion and
T cell activation. Systemic administration of FAP-CAR T cells
effectively suppresses tumor growth in mouse models of ovarian and
lung cancer (103,104). In both human lung cancer
xenografts and murine desmoplastic pancreatic tumors, selective
depletion of FAP+ CAFs by FAP-CAR T cells decreases the
deposition of COL and glycosaminoglycans in the ECM, suppresses
angiogenesis and notably inhibits tumor growth (105). A comparative study further
revealed that FAP-CAR T cells exhibit superior anti-tumor efficacy
relative to CAR T cells targeting a tumor-cell antigen (mesothelin)
in pancreatic ductal adenocarcinoma models (106). Mechanistically, the elimination
of FAP+ CAFs inhibits tumor growth by disrupting the
structural integrity of the desmoplastic matrix and enhancing the
infiltration of endogenous CD8+ T and NK cells (106).
Although FAP-targeted therapy has shown efficacy in
preclinical animal studies, its monotherapy offers limited clinical
benefit (99,107,108). FAP-targeted monotherapy leads to
increased FAP levels in some patients at late stages of treatment,
suggesting the emergence of treatment resistance (109). A potential explanation is that
FAP− CAFs survive during treatment and convert into and
expand as FAP+ CAFs under the influence of other factors
in the TME. Recently, growing evidence indicates that combining
FAP+ CAF-targeting strategies with immunotherapy can
produce combined effects and decrease drug resistance (110-112). In mouse models of colon cancer,
FAP-targeted radiotherapy alone shows substantial activity, whereas
its combination with anti-PD-L1 immunotherapy leads to complete
eradication of all transplanted tumors (108,110). In gastric cancer, FAP-targeted
therapy downregulates PD-L1 expression and upregulates
immunostimulatory cytokines, including IL-2, IL-4, IL-10, IFN-γ and
TNF-α, thereby sensitizing tumors to anti-PD-1 therapy (67). Furthermore, FAP-directed
antibody-drug conjugates (ADCs) enhance the antitumor activity of
ICBs by promoting the intratumoral infiltration of CD8+
cytotoxic T cells (113).
Additionally, combination of FAP-CAR T cells and anti-PD-1 therapy
can exert a combined antitumor effect in pancreatic cancer by
promoting endogenous CD8+ T cell recruitment (114,115). FAP-targeting strategies also
exhibit antitumor activity when combined with chemotherapeutic
agents such as gemcitabine and paclitaxel (113,116). For example, although tumor
regrowth may occur following FAP-targeted ADC monotherapy, its
combination with gemcitabine induces more durable tumor regression
(113). Moreover, the
combination of a FAP-targeted radioligand with an IL-2 antibody
produces stronger antitumor effects compared with either agent
alone (117).
Despite FAP remaining a promising pan-cancer
therapeutic target in clinical translation, its efficacy is limited
in certain patients. This may be attributed to a low baseline
proportion of FAP+ CAFs within the tumor tissue. Careful
assessment of both tumoral and baseline FAP expression in normal
tissues is of critical importance when selecting and implementing
FAP-targeted therapeutic strategies. Understanding of the
mechanisms regulating FAP production and its downstream signaling
pathways may facilitate the identification of more effective
targets for future FAP+ CAF-directed therapy.
Not applicable.
ZT conceived the study and wrote the manuscript. ZZ
constructed tables and figures. YW and JH reviewed and edited the
manuscript. Data authentication is not applicable. All authors have
read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
Not applicable.
No funding was received.
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