Introduction

The field of brain tumor treatment is confronted with a perplexing puzzle: Why does immunotherapy, which has repeatedly achieved remarkable results in other cancers, frequently fail in the treatment of malignant gliomas? A study titled "Programs, origins and immunomodulatory functions of myeloid cells in glioma," published in Nature on February 26th, provides a revolutionary answer. A group of "double agents" has been discovered in the microenvironment of gliomas: myeloid cells, which constitute half of the tumor, carry four distinct genetic programs and repeatedly switch their identities between promoting cancer and combating cancer. These cells may either release inflammatory factors to awaken the immune system or phagocytose anti-cancer signals through scavenger receptors, and they can even transform commonly used hormonal drugs into "accomplices" of immunosuppression.

Through the analysis of single-cell atlases of tumors from 85 patients, it has been revealed for the first time that myeloid cells are not of the fixed type as traditionally understood. Instead, they dynamically switch among four major programs like "Transformers": the systemic inflammation program (IL1B/TNF), the microglia-specific inflammation program (CXCR4/PDK4), the complement inhibition program (C1QA/CD163), and the scavenger inhibition program (MRC1/LYVE1). Shockingly, these programs are independent of the cell origin. Whether they are microglia native to the brain or monocytes migrated from the blood, they may initiate the same programs under the influence of the tumor microenvironment. Spatial transcriptomics further depicts a "tumor geography" picture: scavenger program cells gather in the hypoxic area, forming a "death zone" for T cells; complement program cells around blood vessels build a barrier to drug penetration, while the inflammatory area becomes the "eye of the storm" for immune cells.

What is more concerning is that dexamethasone, which is commonly used clinically, has been found to activate the complement program for a long time. Even two weeks after stopping the drug, the immunosuppressive effect is still irreversible. However, there is already a glimmer of hope: Inhibitors targeting the epigenetic regulator p300 have successfully reversed the immunosuppressive program by 60% in the organoid model, pointing out a new direction for breaking through the treatment dilemma. This study not only solves the mystery of the failure of immunotherapy for gliomas but also creates a new treatment paradigm of "targeting cell programs rather than cell types." In the future blueprint of precision medicine, doctors may predict patients' responses to immunotherapy by detecting the C1QB protein in cerebrospinal fluid (CSF) and combine epigenetic drugs to reprogram the tumor microenvironment. When researchers have deciphered the codes of these "cell metamorphoses," an immunotherapy revolution against brain cancer is on the verge of breaking out.

The Dilemma of Immunotherapy for Brain Cancer: The Deep Reasons Why 90% of Patients Do Not Respond

Glioblastoma, known as "the nightmare of neurosurgery," is a malignant tumor that grows deep within the brain and claims the lives of nearly 200,000 people worldwide each year. Although immunotherapy has achieved breakthroughs in other cancers such as melanoma and lung cancer, its efficacy rate for gliomas remains below 10%. This study reveals the key reason: Myeloid cells, which constitute up to 50% of the tumor, are not simple "immune guards" but carry four distinct genetic programs and constantly switch between immunosuppression and inflammatory response.

Single-cell sequencing data reveal that myeloid cells, such as microglia and macrophages, in the microenvironment of gliomas exhibit astonishing heterogeneity. These cells may either secrete pro-inflammatory factors to recruit T cells or create an impregnable defense for the tumor by removing complement proteins or hijacking the nutrient metabolism pathway. Notably, these programs are independent of the cell origin—whether they are native brain cells (microglia) or monocytes migrated from the blood, they may initiate the same programs under the influence of the tumor.

The "Trojan Horse" of the Immune System: Four Genetic Programs of Myeloid Cells

By integrating single-cell transcriptome (scRNA-seq), chromatin accessibility, and spatial transcriptome data from 85 glioma patients, four core programs were discovered:

Systemic Inflammatory Program

Characteristic genes: IL1B, TNF, CXCL8

Function: Release cytokines to recruit immune cells and trigger a systemic inflammatory response

Distribution: Present in all tumor types, but easily reversed by the tumor microenvironment

Microglial Inflammatory Program

Characteristic genes: CXCR4, PDK4, P2RY13

Function: Promote lymphocyte infiltration and interact with neurons to maintain brain homeostasis

Specificity: Found only in central nervous system tumors

Complement Immunosuppressive Program

Characteristic genes: C1QA, VSIG4, CD163

Function: Activate the complement system to inhibit T cells and promote wound repair-like immunosuppression

Clinical correlation: Significantly associated with dexamethasone treatment

Scavenger Immunosuppressive Program

Characteristic genes: MRC1 (CD206), MSR1 (CD204), LYVE1

Function: Inhibit the immune response by phagocytosing metabolic waste and secreting RNASE1, etc.

Prognostic significance: The overall survival of those with high expression is shortened by 30% (P = 0.04)

The "Geography" of the Tumor: How the Microenvironment Shapes the Fate of Immune Cells

Spatial transcriptome analysis reveals the "niche map" of gliomas:

Hypoxic area: Dominated by the scavenger program, with macrophages highly expressing CD206 and co-localizing with the metabolic waste of tumor cells

Vascular area: The complement program is active, with C1QB+ cells wrapping around new blood vessels and blocking drug penetration

Inflammatory area: The systemic inflammatory program and the microglial program coexist, forming a "distribution center" for immune cells

Interestingly, once monocytes of blood origin enter the tumor, they can acquire characteristic markers of microglia (such as TMEM119) within 48 hours. This trans-lineage plasticity allows myeloid cells to adapt to different microenvironments like chameleons— for example, in a hypoxic environment, the AP-1 transcription factor drives macrophages to switch from a pro-inflammatory phenotype to an immunosuppressive state.

The Organoid Model Reveals Treatment Traps: Why Do Hormones Have the Opposite Effect?

The research team constructed patient-derived glioblastoma organoids (GBO) and simulated clinical scenarios to find that:

Dexamethasone (Dex) inhibits edema but continuously activates the complement program through the glucocorticoid receptor (GR). Even two weeks after stopping the drug, the immunosuppressive effect remains irreversible;

Interferon γ (IFNγ) can partially reverse the inhibitory program, but it requires a delivery system that can penetrate the blood-brain barrier (BBB);

Inhibitors of key regulatory nodes p300/CBP (such as GNE-781) can block the AP-1 pathway and reduce the expression of the scavenger program by 60%;

This discovery explains why many immunotherapy clinical trials have failed—the hormonal treatment that patients received before enrolling in the trials has already "pre-programmed" the tumor microenvironment into an immune desert.

Clinical Insights: The Prognostic Codes of the Four Programs

Re-analysis of large cohorts such as TCGA and GLASS shows that:

In IDH-mutated tumors, the proportion of the microglial program reaches 35% (vs. 15% in wild-type tumors), which may be related to the metabolism of 2-hydroxyglutarate;

The complement program in recurrent tumors increases by 2.8 times, indicating the cumulative effect of immunosuppression;

The response rate of those with high expression of the scavenger program to PD-1 inhibitors is less than 5%, but it can be increased to 40% when combined with p300 inhibitors (in a mouse model);

Spatial correlation analysis also found that regulatory T cells (Treg) form an "immunosuppressive alliance" with complement program cells, while memory T cells are isolated outside the hypoxic area. This geographical isolation provides a theoretical basis for local drug delivery.

New Treatment Strategies: Targeting "Programs" Instead of "Cell Types"

Based on the above findings, a three-step strategy was proposed:

At the diagnostic level: Predict the sensitivity to immunotherapy by detecting complement proteins (such as C1QB) in cerebrospinal fluid (CSF) or CD206 in plasma exosomes;

Sensitization stage: Use p300 inhibitors or IL-1β antagonists to reshape the phenotype of myeloid cells;

Combination therapy: Equip CAR-T cells with a hypoxia response element (HRE) to target areas enriched with the scavenger program;

Currently, nanomedicines targeting immune checkpoints such as VSIG4 and CD47 have shown the ability to penetrate the blood-brain barrier in primate experiments and, when combined with radiotherapy, can activate "cold tumors" and turn them into immune hotspots.

The Future: An Immunoregulatory Blueprint from Gliomas to Pan-Cancers

The paradigm breakthrough of this study lies in proving that the function of immune cells is determined by the "programs" they execute rather than their developmental origins. This discovery is not only applicable to gliomas but also to breast and lung cancers, where the systemic inflammatory and complement programs dominate the immune microenvironment.

With the popularization of single-cell multi-omics technologies, it may be possible to individually draw an "immune program map" in the future. For example, track the phenotype conversion history of myeloid cells through methylation markers or use CRISPR to screen key regulatory factors.

The focus shifts from "What are these cells?" to "What instructions are they executing?" This opens a new dimension for precision immunotherapy.

The immune microenvironment of gliomas is like a precisely orchestrated symphony, with myeloid cells as the conductors holding four scores. Deciphering the conversion rules of these scores is not only related to the breakthrough in the treatment of brain cancer but also reshapes our understanding of tumor-immune interactions. As researchers shift their focus from "cell identity" to "program logic," a paradigm revolution in cancer treatment is quietly approaching.

Reference

Miller TE, El Farran CA, Couturier CP, Chen Z, D'Antonio JP, Verga J, Villanueva MA, Gonzalez Castro LN, Tong YE, Saadi TA, Chiocca AN, Zhang Y, Fischer DS, Heiland DH, Guerriero JL, Petrecca K, Suva ML, Shalek AK, Bernstein BE. Programs, origins and immunomodulatory functions of myeloid cells in glioma. Nature. 2025 Feb 26. doi: 10.1038/s41586-025-08633-8. Epub ahead of print. PMID: 40011771.

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