FAP Fibroblasts: Their Role in Cancer Progression and Disease

Fibroblast activation protein-alpha, commonly called FAP, is a surface enzyme found almost exclusively in diseased tissue, where it marks a subset of stromal cells that actively help tumors grow, spread, and hide from the immune system. In healthy adults, FAP is virtually undetectable, but it appears reliably in conditions involving tissue remodeling such as cancer, fibrosis, and arthritis.¹ That disease-specific expression has made FAP one of the more intensely studied targets in oncology over the past decade, both as a window into how tumors manipulate their surroundings and as a potential weak point that therapies might exploit.

What FAP Actually Is

FAP is a type-II transmembrane serine protease, which means it sits on the outer surface of certain cells and can clip proteins that pass by. It belongs to the same enzyme family as DPP4, a molecule already well known as a drug target in type 2 diabetes, and the two share an unusual structural quirk: the DNA sequence encoding part of their active site is split across two separate stretches of the gene, a feature not seen in classical serine proteases.² The FAP gene sits on chromosome 2 in humans (and in a matching location in mice), and its structure has been conserved across species, hinting that the protein has played an important biological role for a long evolutionary span.

What makes FAP distinctive in oncology is its expression pattern. Normal adult tissues carry little to no FAP. When it does appear, something is wrong: a wound is healing, a joint is inflamed, or a tumor is growing. In cancer specifically, the cells that carry FAP on their surface are cancer-associated fibroblasts, or CAFs. These are not cancer cells themselves. They are stromal support cells that tumors co-opt to build a hospitable microenvironment. CAFs are the most abundant stromal cell type in many solid tumors, and FAP-positive CAFs in particular have been linked to tumor growth, blood-vessel formation, drug resistance, and immune suppression.³

Not All CAFs Are the Same

Researchers used to talk about cancer-associated fibroblasts as if they were one uniform cell type. Single-cell and spatial profiling technologies have demolished that idea. Modern classification schemes identify numerous CAF subtypes based on their protein and gene expression profiles. FAP-positive CAFs alone encompass several subpopulations, including myofibroblast-like CAFs, inflammatory CAFs, antigen-presenting CAFs, and others. Meanwhile, FAP-negative CAFs include vascular-associated fibroblasts, pericytes, and resting fibroblasts.⁴ This diversity matters for treatment. A therapy aimed at FAP-positive fibroblasts will hit several functionally distinct cell subsets while leaving other CAF types untouched. Whether that selective hit is enough to disrupt the tumor’s support network depends on which subtypes are doing the most damage in a given cancer.

How FAP-Positive Fibroblasts Shield Tumors From the Immune System

One of the most consequential things FAP-positive CAFs do is suppress the immune response against cancer cells. In pancreatic cancer, a disease notoriously resistant to immunotherapy, researchers traced the problem to a single signaling molecule called CXCL12. FAP-positive CAFs turned out to be the principal source of CXCL12 in the tumor. The chemokine coated cancer cells and kept T cells physically excluded from the regions where cancer cells lived. When researchers administered a drug that blocks the CXCL12 receptor, T cells quickly flooded into the tumor. Combined with anti-PD-L1 checkpoint therapy, that one-two punch dramatically reduced cancer cell numbers in a mouse model of human pancreatic cancer.⁵

The immune suppression does not stop at T-cell exclusion. FAP-positive fibroblasts also recruit and communicate with other immune cell types in ways that favor the tumor. In prostate cancer, spatial transcriptomics data showed strong associations between FAP-positive fibroblasts and SPP1-positive macrophages, a macrophage subtype linked to immunosuppressive environments. Tumor-specific signaling pathways between these two cell types, including CSF1/CSF1R and CXCL/ACKR1 signaling, appeared to reinforce the suppressive conditions inside the tumor.⁶ In separate work, CAFs were shown to be major producers of chemokines that recruit granulocytes (a type of white blood cell) into tumors. When the CSF1 receptor was blocked therapeutically, this disrupted the signaling between tumor cells and CAFs, triggering a surge of granulocyte infiltration into tumors, which paradoxically can promote tumor-supporting inflammation.⁷

The picture that emerges is one of layered immune suppression. FAP-positive CAFs do not just block a single immune pathway. They orchestrate a network of signals that excludes killer T cells, recruits suppressive immune cell populations, and counteracts the effects of drugs meant to reactivate the immune response. This is a major reason why checkpoint immunotherapies, which work well in some cancers, often fail in tumor types rich in FAP-positive stroma.

Remodeling the Tissue to Help Cancer Spread

Beyond immune evasion, FAP-positive fibroblasts physically reshape the tissue around a tumor. CAFs are the dominant contributors to the extracellular matrix, the structural scaffolding that surrounds cells. In pancreatic cancer, fibroblasts that overexpress FAP produce a matrix with distinct parallel fiber orientations. Pancreatic cancer cells grown on these FAP-remodeled matrices moved faster and with greater directionality compared to cells on normal matrices, suggesting that FAP-positive fibroblasts literally build highways that cancer cells use to invade surrounding tissue.⁸

CAFs also stimulate the formation of new blood vessels. Tumors need a blood supply to grow beyond a small cluster, and fibroblasts within the tumor microenvironment contribute to this by altering the mix of proteins and enzymes in the surrounding tissue.⁹ So FAP-positive CAFs simultaneously open escape routes for cancer cells, supply them with blood, and shield them from immune attack. It is a comprehensive support package.

Feeding the Tumor Through Metabolic Cooperation

One of the more surprising discoveries in recent years is that FAP-positive fibroblasts and cancer cells engage in a metabolic partnership. When fibroblasts are exposed to cancer cells, they undergo metabolic reprogramming: they shift toward producing lactate, which they then export. Neighboring cancer cells take up that lactate and use it as fuel. This exchange, sometimes called the “lactate shuttle,” relies on transporter proteins on both cell types and has been shown to promote cancer cell invasion, migration, and blood-vessel formation in colorectal cancer.¹⁰

In lung adenocarcinoma, researchers found a specific molecular mechanism driving this lactate production. FAP-positive CAFs overexpress a long non-coding RNA called LINC01711, which enhances the activity of an enzyme (LDHA) that produces lactate. LINC01711 does this by facilitating a chemical modification that causes LDHA to assemble into its most active form. The excess lactate does not just feed cancer cells; it also contributes to immunosuppression in the tumor microenvironment. Targeting LINC01711 in preclinical models improved the effectiveness of anti-PD-1 checkpoint immunotherapy, suggesting the metabolic and immune-evasion roles of FAP-positive CAFs are intertwined.¹¹

Making Tumors Resist Treatment

FAP-positive CAFs also contribute to treatment resistance. In esophageal squamous cell carcinoma, culturing cancer cells with material from FAP-positive CAFs significantly increased the cancer cells’ ability to proliferate, migrate, invade, and survive radiation therapy, compared to material from FAP-negative CAFs. The mechanism involved tiny vesicles called exosomes that FAP-positive fibroblasts release into their surroundings. These exosomes carried a long non-coding RNA, AFAP1-AS1, that when absorbed by cancer cells, made them more resistant to radiation damage.¹² This finding underscores that FAP-positive fibroblasts do not need direct contact with cancer cells to influence them. They can send molecular care packages that reprogram distant cancer cells to survive therapies.

Imaging FAP to Find Tumors

The near-absence of FAP in healthy tissue and its reliable presence in tumors have made it an attractive target for diagnostic imaging. A new class of PET (positron emission tomography) tracers called FAPI ligands binds to FAP on the surface of CAFs, allowing clinicians to visualize the tumor microenvironment rather than the cancer cells themselves. Multiple studies have shown that FAPI-PET tracers outperform the standard tracer, FDG, for detecting certain cancers, particularly those known to have low FDG uptake.¹³

A phase 2 trial evaluating one specific FAPI tracer, [68Ga]Ga-FAPI-46, confirmed its safety and its potential as an imaging biomarker for detecting FAP-expressing tumors, with validation against tissue samples taken from the same patients.¹⁴ FAPI-PET is still newer than FDG-PET and not yet universally available, but it represents a conceptual shift. Instead of looking for hungry cancer cells (which is what FDG does, since it is a sugar analog), FAPI-PET looks for the activated stroma that surrounds and supports them. For cancers with dense stromal components, like pancreatic or certain gastrointestinal tumors, this approach can reveal disease that FDG misses.

FAP as a Blood-Based Biomarker

FAP exists not only on cell surfaces but also in a soluble form that can be measured in blood plasma. In colorectal cancer, researchers tracked soluble FAP (sFAP) levels across the progression from normal tissue to adenoma to carcinoma and on to metastatic disease. Lower plasma sFAP levels correlated with poorer survival, suggesting that measuring sFAP could help track disease progression and outcome.¹⁵ The relationship between lower soluble FAP and worse outcomes may seem counterintuitive at first. One explanation is that as tumors grow, more FAP gets trapped in the tissue rather than released into the bloodstream, so a dropping blood level actually reflects increasing stromal FAP activity at the tumor site. This biomarker angle is still being explored, but it offers a non-invasive way to monitor tumor biology without repeated biopsies.

Therapeutic Strategies Targeting FAP

Because FAP sits on the surface of cells that tumors depend on, it has attracted considerable therapeutic interest. The strategies fall into several broad categories, and the history of trying them is instructive about the challenges involved.

Direct Antibodies and Enzyme Inhibitors

The earliest attempts to target FAP clinically were disappointing. Sibrotuzumab, an antibody directed against FAP, entered a phase I dose-escalation trial in patients with advanced cancer. It was well tolerated, with no maximum tolerated dose reached, but there were no objective tumor responses.¹⁶ Val-boroPro (talabostat), a small-molecule inhibitor of FAP’s enzymatic activity, fared similarly in a phase II trial for metastatic colorectal cancer. No objective responses were seen, though about a fifth of patients achieved stable disease for a median of roughly 25 weeks. The study did prove that FAP’s enzymatic activity could be partially suppressed in patients, providing proof of concept even as the clinical benefit remained minimal.¹⁷

These early failures taught the field that simply binding FAP or blocking its enzyme activity is not enough to eliminate the complex support network that FAP-positive CAFs provide. The enzyme’s proteolytic function is only one part of what these fibroblasts do. They also signal through direct cell contact, secrete chemokines, remodel tissue architecture, and shuttle RNA-carrying vesicles. A therapy that only blocks the protease activity leaves the rest of the damage intact.

CAR-T Cells Aimed at Stromal Cells

A more aggressive approach uses engineered immune cells, CAR-T cells, designed to recognize and kill FAP-positive cells. Rather than inhibiting FAP’s function, these therapies physically eliminate the fibroblasts that carry it. Preclinical work in this area has shown promise, and the concept has reached clinical trials.¹⁸ One innovative variation uses bispecific CAR-T cells engineered to recognize both FAP on stromal cells and a second target, GPC3, on cancer cells. In hepatocellular carcinoma models, these dual-targeting CAR-T cells could kill FAP-positive fibroblasts, GPC3-positive cancer cells, and cells expressing both markers, addressing tumor heterogeneity more effectively than a single-target approach.¹⁹

Bispecific Antibodies and Bystander Killing

Another promising approach bypasses the need to engineer patient cells ex vivo. Bispecific antibodies are designed to grab FAP on one arm and a T-cell receptor component (CD3) on the other, physically bringing a patient’s own T cells into contact with FAP-positive fibroblasts. OMTX305 is one such molecule, a trivalent bispecific antibody that has been tested in patient-derived tumor slice models of lung and ovarian cancer. Treatment with OMTX305 eliminated FAP-expressing fibroblasts and triggered an interferon response and extracellular matrix remodeling in the surrounding tissue. Most intriguingly, the killing was not limited to the fibroblasts themselves. Adjacent tumor cells also died through a bystander effect, suggesting that dismantling the stromal scaffold can destabilize cancer cells that depend on it.⁴

The Safety Problem With Destroying FAP-Positive Cells

Enthusiasm for eliminating FAP-positive cells is tempered by a significant safety concern. FAP is rare in healthy adult tissue, but it is not absent everywhere. Small populations of FAP-expressing stromal cells exist in skeletal muscle and bone marrow, where they play essential housekeeping roles. In mouse experiments, when FAP-positive cells were depleted from the entire body rather than just from tumors, animals developed muscle wasting (cachexia) and reduced production of red blood cells and B-lymphocytes in the bone marrow.²⁰ These are serious toxicities, and they explain why global FAP-cell depletion is not a viable strategy. Therapies need to be selective enough to hit FAP-positive CAFs inside tumors without wiping out the small but important FAP-positive populations in muscle and marrow. Achieving that selectivity, whether through localized delivery, conditional activation, or careful dosing, remains an active area of research.

FAP Beyond Cancer

FAP is not exclusively a cancer story. Any disease involving activated fibroblasts and tissue remodeling can feature FAP expression. In rheumatoid arthritis, fibroblast-like synoviocytes in inflamed joints abundantly express FAP, where it contributes to immune activation, inflammation, tissue invasion, and the growth of new blood vessels in the joint lining.²¹ FAP is also upregulated in cardiovascular disease: at sites of tissue remodeling including atherosclerotic plaques and fibrotic hearts. In an experimental atherosclerosis model, deleting FAP provided a protective effect against plaque development.²²

These non-cancer roles have two implications. First, they mean FAPI-PET imaging is not perfectly cancer-specific. An inflamed joint or a healing wound could produce a signal, which is something clinicians need to account for when interpreting scans. Second, they open the possibility that therapies developed for cancer-associated FAP might eventually find applications in arthritis, fibrosis, or cardiovascular disease. The biology overlaps more than the clinical silos suggest.

Why Early Inhibitors Failed and What Changed

The trajectory from sibrotuzumab’s failure in the early 2000s to today’s bispecific antibodies and dual-target CAR-T cells reflects a broader shift in how oncology thinks about the tumor microenvironment. Early approaches treated FAP as a single-target problem. Block the enzyme, shrink the tumor. That did not work because FAP-positive fibroblasts contribute to cancer through so many parallel channels: immune suppression via CXCL12, metabolic support via the lactate shuttle, physical tissue remodeling, vesicle-mediated transfer of resistance-promoting RNA, and recruitment of immunosuppressive immune cells. Blocking one of those channels leaves the others intact.

The newer strategies are more aggressive and more nuanced. Killing FAP-positive cells outright (with CAR-T cells or bispecific antibodies) eliminates multiple channels at once. Combining FAP-targeting with checkpoint immunotherapy attacks the immune evasion problem from two directions simultaneously. And the recognition that FAP-positive fibroblasts cooperate with specific macrophage subtypes and granulocyte populations has opened up possibilities for combination regimens that disrupt several tumor-supporting partnerships at the same time. The field has moved from viewing FAP as a single molecular target to understanding it as a marker of a cell type that orchestrates tumor support, which demands a fundamentally different therapeutic philosophy.