The Metabokine Checkpoint: Targeting ANGPTL3 to Overcome Anti-PD-1 Resistance in Gastric Cancer

Immune checkpoint blockade (ICB), particularly targeting the PD-1/PD-L1 axis, has redefined the treatment landscape for advanced gastric cancer (AGC). However, the clinical reality remains sobering: only approximately 15% of patients derive durable benefit from anti-PD-1 monotherapy. The majority of patients exhibit primary or adaptive resistance, often characterized by "cold" tumor microenvironments (TMEs) lacking sufficient cytotoxic T-cell infiltration.

In a landmark 2026 study published in Cancer Research Communications, Kudo-Saito et al. utilize comprehensive proteomic profiling to identify a novel "villainous molecule", Angiopoietin-like 3 (ANGPTL3), that acts as a soluble checkpoint bridging lipid metabolism and immune evasion. By leveraging high-quality in vivo reagents to model this biology, the authors demonstrate that ANGPTL3 blockade can synergize with anti-PD-1 therapy to reprogram the immune landscape, offering a new avenue for patients resistant to current standards of care.

The search for predictive biomarkers in ICB has largely focused on tumor mutational burden or PD-L1 expression, both of which have limitations. Kudo-Saito and colleagues took a broader approach, performing proteomic analysis on plasma from 91 AGC patients receiving nivolumab.

Comparing responders to non-responders, they identified ANGPTL3 as a significant outlier. Traditionally known for its role in lipid metabolism (inhibiting lipoprotein lipase), ANGPTL3 was found to be dramatically upregulated, over 30-fol, in the post-treatment plasma of patients with progressive disease. Furthermore, high baseline levels of ANGPTL3 were statistically associated with significantly shorter Progression-Free Survival (PFS) and Overall Survival (OS).

To move from clinical correlation to therapeutic causation, the authors utilized the Colon26 murine colon cancer model implanted subcutaneously in BALB/c mice. This phase of the study was designed to test whether blocking ANGPTL3 could overcome resistance to standard checkpoint blockade.

The study relied specifically on ichorbio’s Anti-ANGPTL3 antibody (Catalog #ICH5151) as the primary experimental therapeutic. To rigorously test synergy, the researchers established a treatment protocol dosing the mice at 10 mg/kg on days 3 and 10 post-implantation. They compared the efficacy of the ichorbio anti-ANGPTL3 antibody against a standard Anti-PD-1 antibody (Clone 29F.1A12) and a Mouse IgG isotype control.

The in vivo therapy experiments yielded compelling results (Figure 4 of the study):

1. Monotherapy Limitations: Treatment with anti-PD-1 alone or anti-ANGPTL3 alone resulted in only modest tumor growth inhibition.

2. Combination Synergy: The concurrent administration of anti-PD-1 and anti-ANGPTL3 significantly inhibited tumor growth (P=0.001) and increased the number of tumor-free mice.

This synergy implies that ANGPTL3 blockade does not merely kill tumor cells directly but functions as an immunosensitizer, rendering the tumor susceptible to checkpoint blockade.

Flow cytometric analysis of the tumor-infiltrating lymphocytes (TILs) revealed how ANGPTL3 blockade remodels the TME. The combination therapy led to a profound shift in the immune composition:

• Restoration of Cytotoxicity: There was a significant increase in the infiltration of CD8+ cytotoxic T cells and Natural Killer (NK) cells.

• Myeloid Repolarization: Concurrently, there was a reduction in immunosuppressive myeloid populations, specifically CD11b+CD11c+ cells and M2-like macrophages.

This suggests that ANGPTL3 functions as an immune checkpoint that, when present, maintains the TME in an immunosuppressive, M2-dominant state that excludes effector T cells, a hallmark of "cold" tumors.

The identification of ANGPTL3 as a resistance factor has immediate translational implications:

1. Liquid Biopsy Biomarker: As a secreted protein detectable in plasma, ANGPTL3 offers a non-invasive method to stratify patients. High levels could serve as a "stop" signal for anti-PD-1 monotherapy, sparing non-responders from toxicity and directing them toward alternative trials.

2. Metabolic-Immune Crosstalk: This study reinforces the concept of "metabokines", molecules that link metabolic dysregulation (common in cancer) with immune evasion. It opens the door to repurposing metabolic drugs or developing bispecifics that target this intersection.

3. Combination Strategy: The synergy observed with PD-1 blockade suggests that ANGPTL3 inhibitors could be ideal partners for existing checkpoint inhibitors, particularly in gastric and colorectal cancers which are often refractory to treatment.

While the study establishes efficacy, the precise molecular mechanism remains to be fully elucidated. The authors and other researchers could consider the following experiments to deepen the understanding of this pathway:

• Fc-Engineering Studies: To determine if the anti-ANGPTL3 effect relies on Fc-mediated effector functions (like ADCC/ADCP) or simple ligand neutralization, the authors could repeat the Colon26 therapy using ichorbio’s LALA-PG (Low Endotoxin, Silenced Fc) variants of the anti-ANGPTL3 antibody. If the silenced antibody loses efficacy, it would suggest that macrophage depletion via Fc-gamma receptors is the primary mechanism.

• Receptor Identification: The specific receptor on myeloid cells that ANGPTL3 binds to exerts its immunosuppressive effect is currently unknown. CRISPR-screening or receptor-ligand capture assays on M2 macrophages in the presence of recombinant ANGPTL3 could identify this "metabolic checkpoint" receptor.

• Metabolic vs. Immune Dissection: Given ANGPTL3's role in lipid metabolism, it is crucial to disentangle systemic lipid changes from local immune effects. Experiments using specific lipid-lowering agents (e.g., evinacumab) versus immune-sequestering antibodies could clarify if the tumor control is driven by starving the tumor of lipids or by directly unlocking the immune system.

Kudo-Saito C, Shoji H, Nagashima K, Imazeki H, Tsugaru K, Takahashi N, Kawakami T, Amanuma Y, Wakatsuki T, Okano N, Narita Y, Yamamoto Y, Kizawa R, Muro K, Boku N. ANGPTL3 in the peripheral circulation is associated with resistance to anti-PD1 therapy in advanced gastric cancer. Cancer Res Commun. 2026 Jan 30. doi: 10.1158/2767-9764.

Link to Cancer Research Communications Paper