Tertiary lymphoid structures are clusters of immune cells that form in tissues where they do not normally exist, assembling on the spot in response to chronic inflammation, infection, or cancer. Unlike lymph nodes, which develop before birth and stay in fixed locations, these structures arise spontaneously in adult tissue and can either help fight disease or fuel it, depending on context. In tumors, their presence is one of the strongest predictors of a good response to immunotherapy, yet in autoimmune conditions and transplanted organs, the same structures can drive destructive immune attacks. That dual personality is what makes them one of the most actively studied features in modern immunology.
What Tertiary Lymphoid Structures Actually Are
Your body has a built-in network of immune hubs called lymph nodes and the spleen, which are formally known as secondary lymphoid organs. These are wired in during fetal development, wrapped in capsules, and located in predictable spots. Tertiary lymphoid structures share much of the same internal architecture, with zones where T cells and B cells congregate, but they differ in important ways: they lack a surrounding capsule, they appear only after sustained immune stimulation, and they can pop up nearly anywhere, from the lining of the gut to deep inside a tumor mass.1PubMed Central. The roles of tertiary lymphoid structures in chronic diseases
Formation begins when immune cells release signaling molecules, particularly chemokines like CXCL13 and CCL21, that recruit B cells and T cells to a specific site. Specialized blood vessels called high endothelial venules develop at the same location, acting as gateways that ferry fresh immune cells from the bloodstream directly into the growing structure.2PubMed. High endothelial venules in cancer: Regulation, function, and therapeutic implication Over time, if the inflammatory signal persists, the loose cluster can mature into a highly organized structure complete with a germinal center, the zone where B cells undergo the rapid mutation and selection process that produces highly targeted antibodies.
Maturation Makes the Difference
Not all tertiary lymphoid structures are created equal. Researchers describe them along a maturation spectrum, from early, disorganized aggregates of immune cells to fully mature structures with active germinal centers. Where a structure falls on that spectrum turns out to matter enormously for its effect on disease. Mature structures with well-developed germinal centers show a far stronger capacity to suppress tumors than their immature counterparts.3PubMed Central. Tertiary lymphoid structures in cancer: maturation and induction
Inside a mature germinal center, B cells go through rounds of mutation and competitive selection. The winners are clones whose antibodies bind most tightly to a target, whether that target is a virus, a bacterium, or a protein on a cancer cell. Those winning B cells then mature into plasma cells that churn out large quantities of antibodies. In cancer, this means a mature tertiary lymphoid structure can act as a local antibody factory trained against the tumor itself. Immature structures, lacking that germinal center machinery, contribute far less to anti-tumor immunity, which is why simply counting these structures without assessing their maturity can give a misleading picture.
The Cancer Connection
The link between tertiary lymphoid structures and cancer outcomes has been documented across a wide range of tumor types. A meta-analysis pooling data from solid tumors found that patients with high expression of these structures had roughly a third lower risk of death and about 40% lower risk of recurrence compared to patients with low expression.4PubMed Central. Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors That association holds across cancers of the lung, colon, breast, kidney, and several others.
The reason for this benefit appears to involve both arms of the adaptive immune system. T cells within and around these structures can directly kill cancer cells. But B cells play a role that was underappreciated until recently. Within the germinal centers of mature structures, B cell clones undergo antibody class switching and somatic hypermutation, then differentiate into plasma cells that produce antibodies targeting tumor-associated proteins.5PubMed. B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome In kidney cancer specifically, researchers have traced the full journey: B cells mature inside the tumor, produce antibodies (mostly of the IgG type) that bind to cancer cells, and those antibody-coated cells then undergo a form of programmed death. Macrophages in the vicinity appear to help carry out this killing.6Immunity. Tertiary lymphoid structures improve immunotherapy and response in patients with renal cell carcinoma Patients with the highest number of antibody-coated tumor cells had better responses to checkpoint immunotherapy and longer progression-free survival.
A Biomarker for Immunotherapy Response
The explosion of interest in tertiary lymphoid structures over the past few years largely stems from their value as predictors of who will respond to immunotherapy. Checkpoint inhibitors, the drugs that release the brakes on T cells, work far better in some patients than others. The presence of mature structures appears to be one of the most reliable markers of a favorable response, and it works independently of other commonly used markers like PD-L1 expression and the density of T cells that have infiltrated the tumor.7PubMed Central. Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression
Two separate meta-analyses have quantified this advantage. One found that cancer patients treated with checkpoint inhibitors who had high levels of these structures had roughly half the risk of disease progression and about a third the risk of death compared to those with low levels.8PubMed Central. Association between tertiary lymphoid structures and clinical outcomes in cancer patients treated with immune checkpoint inhibitors: an updated meta-analysis A second meta-analysis reported similarly favorable associations, with high intratumoral levels linked to about a third lower risk of death and roughly 40% lower risk of progression during immunotherapy.9PubMed Central. The predictive value of intratumoral tertiary lymphoid structures on the response to immunotherapy in cancer patients: a systematic review and meta-analysis The specific numbers differ somewhat between these analyses because they include different study populations and time periods, but the direction and magnitude are consistent: more structures, better outcomes.
In melanoma, a gene signature associated with these structures predicted clinical outcomes in patients receiving checkpoint blockade, suggesting that even when you cannot directly look at the tissue under a microscope, molecular markers of their presence carry prognostic weight.10Nature. Tertiary lymphoid structures improve immunotherapy and survival in melanoma
When the Structures Work Against You
The story changes sharply in autoimmune diseases. In conditions like rheumatoid arthritis, Sjögren syndrome, and certain types of thyroid disease, tertiary lymphoid structures form in the affected organs and sustain the very immune responses that are damaging healthy tissue. They provide a local environment where autoreactive immune cells, the ones that mistakenly attack the body’s own proteins, can survive, multiply, and produce pathogenic autoantibodies. Detection of these structures in autoimmune tissue is generally associated with worse disease and a more aggressive course.11PubMed Central. Tertiary Lymphoid Structures: Autoimmunity Goes Local
The same principle applies in chronic age-related inflammatory diseases, including chronic kidney disease. In these settings, the structures correlate with more severe disease rather than protection.1PubMed Central. The roles of tertiary lymphoid structures in chronic diseases The structures also contribute to host defense during infectious diseases, which is a benefit, but the broader pattern is clear: these immune hubs amplify whatever immune response is already under way.12PubMed Central. The roles of tertiary lymphoid structures in orchestrating immune responses in peripheral organs If that response is aimed at a tumor or a pathogen, amplification helps. If it is aimed at the body’s own tissues, amplification hurts.
The Organ Transplant Problem
Transplant rejection offers a particularly striking example. In a mouse model of kidney transplantation, researchers found that preformed tertiary lymphoid structures in a donor organ were sufficient to trigger rejection all on their own. Grafts containing these structures were rejected with a mean survival time of just 23 days, while matched grafts lacking them survived beyond 200 days. The structures supported a complete immune attack, activating both T cells and B cells and producing donor-specific antibodies.13The Journal of Clinical Investigation. Lymphotoxin β receptor and tertiary lymphoid organs shape acute and chronic allograft rejection For transplant medicine, this suggests that the presence of these structures in a donor organ or at a graft site is a red flag that could help predict rejection risk.
Even in Cancer, Not Always Helpful
The general rule that tertiary lymphoid structures predict better cancer outcomes has notable exceptions. Regulatory T cells, the immune cells whose job is to suppress other immune cells, can infiltrate these structures and effectively neutralize them. In a genetically engineered mouse model of lung cancer, more than 90% of tumors had associated tertiary lymphoid structures, but regulatory T cells within those structures were suppressing anti-tumor T cell responses. When the regulatory T cells were depleted, the immune response ramped up and tumors shrank.14PubMed Central. Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses
In human non-small-cell lung cancer, regulatory T cells found inside the structures expressed different surface markers compared to those found outside, suggesting that the local environment shapes which kind of regulatory T cell takes up residence.15PubMed Central. Regulatory T cells infiltrate the tumor-induced tertiary lymphoïd structures and are associated with poor clinical outcome in NSCLC And in a rare form of cervical cancer, researchers found that mature structures were associated with increased infiltration of regulatory T cells and regulatory B cells, creating an immunosuppressive environment rather than an anti-tumor one. In that setting, the structures correlated with worse outcomes.16JNCI: Journal of the National Cancer Institute. An immunosuppressive tertiary lymphoid structure is associated with adverse prognosis in gastric-type endocervical adenocarcinoma
These exceptions are important because they caution against treating the presence of tertiary lymphoid structures as an automatic “good sign” in every cancer patient. The composition of the structure, particularly the balance between effector immune cells and suppressive ones, may matter as much as whether the structure is there at all.
Trying to Build Them on Purpose
If tertiary lymphoid structures help the immune system fight cancer, an obvious therapeutic question follows: can you engineer their formation where they do not naturally appear? Multiple research groups are now trying exactly that, using approaches ranging from injectable biomaterials to engineered viruses.
One approach uses biodegradable hydrogels loaded with the same chemokine signals that drive natural formation. In a mouse melanoma model, researchers packed four key signaling molecules into lipid-coated microparticles embedded in a gel that, once injected, slowly released its payload over several days. The injected sites developed immune cell clusters rich in B cells and T cells, and these induced structures suppressed tumor growth by promoting tumor-specific T cell responses.17PubMed Central. Chemokine/cytokine-releasing biomaterials induce in situ tertiary lymphoid-like structures and enhance antitumor immunity
A separate team used CXCL13 and CCL21, two of the same chemokines, administered alongside an anti-PD-L1 checkpoint inhibitor in a melanoma model. Mice that received the chemokine combination during immunotherapy developed significantly more structures and showed better tumor suppression than those receiving the checkpoint inhibitor with only one of the chemokines.18PubMed Central. CXCL13 and CCL21 Induce Tertiary Lymphoid Structures and Enhance the Efficacy of Immunotherapy for Melanoma The idea is that combining a checkpoint inhibitor with signals that recruit immune cells into organized structures could amplify the therapeutic effect beyond what either strategy achieves alone.
Other groups are exploring even more creative platforms. Covalent organic frameworks, a type of synthetic porous material, have been used to trigger structure formation through phototherapy that stimulates immune-cell-recruiting cytokine production.19PubMed Central. Trigger inducible tertiary lymphoid structure formation using covalent organic frameworks for cancer immunotherapy STING agonists, compounds that activate an innate immune sensing pathway, have been shown to induce formation in melanoma while simultaneously normalizing the tumor’s blood vessels, making it easier for immune cells to get in.20PubMed Central. STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment The broader landscape of biomaterial strategies now includes nanocarriers, stimulus-responsive hydrogels, 3D scaffolds, exosomes, engineered immune cells, oncolytic viruses, and bacteria.21PubMed. Tailored Biomaterials Induce Tertiary Lymphoid Structures for Boosting Cancer Immunotherapy All of this remains preclinical, in mouse models. But the speed of development suggests clinical trials are likely not far off.
Chemotherapy itself can sometimes promote formation. In liver cancer, a specific chemotherapy regimen delivered directly into the liver’s arterial blood supply was shown to enhance the formation of these structures in tumor tissue. The mechanism involved chemotherapy triggering a particular subset of T cells to produce signals that activated supporting cells, including fibroblasts and macrophages, which in turn built the structural scaffolding for immune cell organization. Patients whose tumors developed more structures after treatment had longer progression-free survival.22Cell Reports Medicine / PubMed Central. Enhanced formation of tertiary lymphoid structures shapes the anti-tumor microenvironment in hepatocellular carcinoma after FOLFOX-HAIC therapy
Detecting Them Without Surgery
A persistent practical challenge is that identifying tertiary lymphoid structures currently requires tissue from a biopsy or a surgically removed tumor, examined under a microscope or analyzed with molecular tools. That limits their usefulness as a real-time biomarker. Several groups are working on ways to detect them noninvasively.
In gastric cancer, researchers developed a CT-based scoring system that classifies tumors into four categories based on imaging features associated with the structures. The model was designed to predict both their presence and the patient’s likely response to immunotherapy.23Clinical Cancer Research. Noninvasive Imaging Assessment of Tertiary Lymphoid Structures and Immunotherapy Response in Gastric Cancer: A Multicenter Study In pancreatic cancer, PET/CT scans using a standard glucose tracer have shown promise as a tool for assessing the presence of these structures and predicting anti-tumor immunity without the need for a tissue sample.24PubMed Central. Assessment of tertiary lymphoid structures via (18)F-FDG PET/CT scan in patients with pancreatic adenocarcinoma
On the molecular side, spatial transcriptomics is transforming the field’s understanding of what happens inside and around these structures. A pan-cancer spatial atlas spanning 12 cancer types has mapped the architecture and maturation states of tertiary lymphoid structures at single-cell resolution, revealing that maturation is accompanied by coordinated remodeling of surrounding cell populations and distance-dependent shifts in the tumor’s own gene expression.25PubMed. Pan-cancer spatial atlas of tertiary lymphoid structures Complementary work using high-plex spatial molecular imaging has developed computational methods to characterize the structures and distinguish mature structures from earlier lymphoid aggregates across nine cancer types.26Cancer Research. Abstract 1152: Pan-cancer single-cell and subcellular characterization of lymphoid aggregates and tertiary lymphoid structures using high-plex spatial molecular imaging
The Gut Microbiome Connection
An emerging line of research links the composition of gut bacteria to whether and how robustly these structures form in tumors. The gut microbiome is already known to influence responses to cancer immunotherapy, and one mechanism appears to involve tertiary lymphoid structures as an intermediary. In a colorectal cancer model, colonization of the gut with a particularly immunogenic bacterium modified the behavior of colon-resident T cells, driving the formation of tertiary lymphoid structures in the tumor and enhancing anti-tumor immunity.27Immunity. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and antitumor immunity against colorectal cancer The implication is that the immune effect depended heavily on which bacterial species was introduced, meaning that gut microbiome composition could be one reason some patients develop robust structures in their tumors and others do not.
More broadly, researchers are exploring whether manipulating the microbiome, through probiotics, fecal transplantation, or metabolite supplementation, could serve as yet another way to encourage structure formation and improve responses to immunotherapy.28PubMed Central. Exploring effects of gut microbiota on tertiary lymphoid structure formation for tumor immunotherapy The evidence here is still largely correlational and drawn from animal models, but the thread connecting diet, gut bacteria, immune organization, and tumor outcomes is becoming difficult to ignore.
Metabolism and Structure Formation
How the cells inside a tumor generate and use energy also appears to influence whether tertiary lymphoid structures form. The metabolic environment of a tumor is notoriously abnormal: cancer cells consume glucose at high rates, acidify their surroundings, and create conditions that can starve immune cells of the nutrients they need. Immune cells that drive the formation of germinal centers, particularly a specialized subset of T helper cells, are sensitive to these metabolic conditions. Disruptions in glucose, lipid, amino acid, and even vitamin metabolism within the tumor microenvironment have all been linked to changes in the formation of the cellular building blocks needed for mature structures.29PubMed Central. The impact of metabolic reprogramming on tertiary lymphoid structure formation: enhancing cancer immunotherapy The evidence connecting metabolism directly to structure formation is still being built, and much of the current work focuses on associations rather than proven cause-and-effect pathways. But the metabolic angle opens an intriguing therapeutic possibility: if the metabolic hostility of a tumor can be softened, perhaps through drugs that target tumor metabolism, it might become easier for the immune system to organize itself into the structures that correlate with better outcomes.