Journal for immunotherapy of cancerOct 21, 2025

Macrophages with high SPP1 cause T-cell stress that may help colon cancer spread to the liver through the SPP1/CD44/PI3K/AKT pathway

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Updated Mar 10, 2026

Abstract

Liver metastatic lesions exhibited a significantly elevated infiltration of exhausted T cells compared with primary tumors.

Exhausted T cells showed increased expression of exhaustion-related marker genes such as ANK3, ZBTB20, ETV6, and CAMK4 in liver metastases.
A distinct T-cell subset, characterized by high levels of HSPA1A and HSPA1B, was identified as an intermediate state between effector and exhausted T cells.
Myeloid cells expressing high levels of (SPP1) were associated with poor prognosis in patients with colon cancer liver metastases.
SPP1 myeloid cells were found to reduce T-cell populations and induce a stress response in CD4 and CD8 T cells via a specific signaling pathway.
Combination treatment with anti-SPP1 and anti-PD-1 antibodies significantly inhibited liver metastasis growth and enhanced T-cell function.

Simplified

BACKGROUND: Patients with colon cancer liver metastases (CCLM) frequently exhibit poor responses to immunotherapy, a phenomenon attributed in part to an immune desert tumor microenvironment. This study aimed to comprehensively characterize the immune landscape in primary colon cancers and their matched liver metastases via single-cell transcriptome analysis, with the goal of identifying potential immunotherapeutic targets.

METHODS: Tumor specimens from patients with CCLM were subjected to single-cell RNA sequencing. Immune subpopulations were profiled with emphasis on exhausted T cells (Tex)-including both CD8and CD4ANK3subsets-as well as on a distinct stress response T-cell subset () defined by high HSPA1A/HSPA1B expression. In parallel, we performed assessments of the phenotype and prognostic impact of SPP1myeloid cells, along withassays to examine their role in modulating T-cell number and function. + + + high in vitro

RESULTS: Liver metastatic lesions exhibited a significantly elevated infiltration of Tex compared with primary tumors. Notably, Tex cells exhibited upregulated expression of exhaustion-related marker genes such as ANK3, ZBTB20, ETV6, and CAMK4, which were markedly downregulated in TSTR cells. TSTR was identified as an intermediate developmental state between effector and exhausted T cells in patients with CCLM, suggesting that TSTR cells represent a distinct state from exhausted T cells. Furthermore, myeloid cells expressing high levels of (SPP1), along with apolipoprotein C-I and apolipoprotein E, were associated with poor prognosis in patients with CCLM.studies revealed that Macro_SPP1cells diminished T-cell populations and triggered a stress response state in both CD4and CD8T cells via the SPP1/CD44/PI3K/AKT signaling pathway in a CD44-dependent manner. Importantly, combination treatment with anti-SPP1 and anti-programmed cell death protein-1 antibodies significantly inhibited liver metastasis growth, enhanced dendritic cell maturation, decreased M2-polarized macrophages, and restored T-cell infiltration and function. In vitro high + +

CONCLUSIONS: These findings reveal a previously unrecognized relationship between Macro_SPP1cells and HSPA1A/HSPA1BT cells in driving CCLM progression, suggesting a potential synergistic therapeutic approach that could boost immune checkpoint treatment efficacy in patients with CCLM. high high high

Key numbers

significantly higher in liver metastases vs. primary tumors

Infiltration of exhausted T cells

Comparison of T-cell populations in liver metastases and primary colon cancer.

5 mg/kg body weight for each antibody

Combination therapy effectiveness

Dosing regimen for therapeutic antibodies in combination therapy.

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Macrophages with high SPP1 cause T-cell stress that may help colon cancer spread to the liver through the SPP1/CD44/PI3K/AKT pathway

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