# Prognostic integration of tumor microenvironment and parthanatos-related genes in gastric cancer: a machine learning-driven risk model and immune landscape profiling

## TL;DR

This study combines tumor microenvironment and parthanatos-related genes to build a machine learning model for predicting gastric cancer prognosis and immune response.

## Contribution

The study introduces a novel machine learning model integrating TME and parthanatos-related genes for gastric cancer prognosis and identifies CD36/KIT as potential therapeutic targets.

## Key findings

- A machine learning model using seven genes (EGF, PCOLCE2, CD36, ADAMTS8, CIDEC, KIT, AKAP12) effectively stratifies gastric cancer patient risk.
- High-risk patients exhibit immunosuppressive tumor microenvironments and poor immunotherapy response.
- CD36/KIT inhibition reduces cancer cell proliferation and activates the parthanatos pathway, inducing cell death.

## Abstract

The tumor microenvironment (TME) plays a pivotal role in the progression of gastric cancer (GC) and its response to treatment, particularly by modulating parthanatos (PA). However, the prognostic significance of TME and PA, as well as their potential roles in immunotherapy for GC, remain incompletely understood.

Using publicly available data, an initial gene screening was combined with differential expression analysis and univariate Cox regression to identify prognostic markers associated with TME and PA. A comprehensive machine learning framework, testing 101 algorithm combinations across 10 methodologies, was then applied. Model selection prioritized C-index performance, with the final model enabling effective patient risk stratification, as validated by Receiver Operating Characteristic (ROC) curves. Multivariate analysis subsequently identified independent prognostic factors, which were used to construct a clinical nomogram. Immune characteristics across different risk groups were compared, immunofluorescence staining of gastric cancer and paired paracancerous tissues assessed immune cell infiltration and prognostic gene-monocyte correlation. Biomarker expression patterns were confirmed via Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) validation. Immunohistochemical (IHC) detected CD36/KIT protein expression. CCK-8, Transwell and flow cytometry evaluated proliferation, migration and apoptosis in CD36/KIT inhibitor-treated GC MKN45 cells. Enzyme-linked immunosorbent assay (ELISA) measured TNF-α, IFN-γ, IL-10 secretion; immunofluorescence determined PARP-1/AIFM1 subcellular localization post-inhibitor treatment.

The multi-algorithm analysis identified the RSF-plsRcox hybrid model as the most accurate, consistently achieving C-index values greater than 0.6 across all datasets. This model identified seven clinically significant genes (EGF, PCOLCE2, CD36, ADAMTS8, CIDEC, KIT, and AKAP12) with notable prognostic value in GC progression. The developed risk model demonstrated good predictive performance, with areas under the curve (AUCs) of 0.65, 0.68, and 0.60 at 1, 3, and 5 years, respectively. A nomogram based on independent prognostic factors—risk scores, age, N stage, and M stage—showed strong predictive accuracy, with AUCs of 0.72, 0.75, and 0.71 at 1, 3, and 5 years, respectively. Furthermore, distinct immune landscapes were observed between high-risk and low-risk groups, characterized by differences in immune infiltration, immune checkpoint expression, and TIDE scores. Gastric cancer tissues had reduced CD3+T, CD3+CD4+T cells and M1 macrophage infiltration, increased M2 macrophages and CD14+monocytes; AKAP12 was positively correlated with monocytes. The higher-risk group exhibited suppressed immune responses and enhanced immune evasion capabilities. RT-qPCR validation revealed significant differential expression of PCOLCE2, CD36, ADAMTS8, and KIT in the control group, while AKAP12 was more highly expressed in the GC group. These five prognostic genes showed significant expression differences between the two groups (P < 0.05).CD36 and KIT protein expression was elevated in gastric cancer tissues. CD36/KIT inhibition downregulated their expression in MKN45 cells, inhibiting proliferation, migration and promoting apoptosis. Inhibition increased TNF-α, IFN-γ secretion, decreased IL-10, enhanced nuclear PARP-1 fluorescence and AIFM1 nuclear translocation.

This study innovatively integrated TME-RGs and PA-RGs to construct a machine learning GC prognostic model (7 key genes: EGF, PCOLCE2, CD36, ADAMTS8, CIDEC, KIT, and AKAP12). High-risk patients had immunosuppressive TME and poor immunotherapy response, with Imatinib/PLX4720 showing potential efficacy. CD36/KIT overexpression promoted GC malignancy; their inhibition remodeled TME cytokines and, for the first time, activated the PA pathway to induce GC cell death.