# Autophagy Modulates Immunogenic Cell Death in Cancer

## TL;DR

This review explores how autophagy influences immunogenic cell death in cancer, especially in hematological malignancies like multiple myeloma.

## Contribution

The paper provides a comprehensive overview of how autophagy modulates immunogenic cell death in a context-dependent manner across different cancers.

## Key findings

- Autophagy can both promote and inhibit immunogenic cell death depending on the tumor context and pathway steps.
- In multiple myeloma, the autophagy-related protein GABARAP is involved in bortezomib-induced immunogenic cell death.
- Modulating autophagy could improve immunotherapies by enhancing the release of damage-associated molecular patterns.

## Abstract

Immunogenic cell death (ICD) is a form of regulated cell death that could change a “cold” tumor into an immune-inflamed “hot” tumor by exposing and releasing damage-associated molecular patterns (DAMPs). Recent works indicate that autophagy can either facilitate or inhibit ICD, depending on the context and which step of the pathway is targeted. In this review, we summarize the current knowledge on the autophagy–ICD axis in various kinds of cancer, and we then focus on hematological malignancies, especially multiple myeloma, in which autophagy and ICD play important roles. We propose how the phase-specific modulation of autophagy could be exploited to design novel immunogenic chemotherapy combinations and improve cellular immunotherapies.

Immunogenic cell death (ICD) is a subtype of regulated cell death characterized by the spatiotemporally coordinated emission of damage-associated molecular patterns (DAMPs), such as calreticulin (CALR), ATP, and high-mobility group box-1 (HMGB1), which collectively prime tumor-specific T-cell responses. Autophagy, a lysosome-dependent catabolic process, is increasingly recognized as a key modifier of antitumor immunity and the tumor microenvironment (TME). In preclinical models, autophagy can not only promote ICD by sustaining endoplasmic reticulum (ER) stress, eukaryotic translation initiation factor-2α (eIF2α) phosphorylation, and secretory pathways, but it can also limit ICD by degrading DAMPs, antigenic cargo, and major histocompatibility complex (MHC) molecules. The net outcome is highly context-dependent and determined by the tumor type, the nature and intensity of the stress, and the level at which autophagy is modulated. Herein, we summarize how autophagy affects the three canonical ICD-associated DAMPs, highlight solid-tumor models in which autophagy supports ICD, and contrast them with systems wherein autophagy inhibition is required for immunogenicity. We then focus on hematological malignancies, especially multiple myeloma, where recent reports implicate the autophagy-related protein GABARAP in bortezomib-induced ICD. Finally, we discuss the translational implications, including rational combinations of autophagy modulators with ICD-inducing chemotherapies, targeted drugs, and cellular immunotherapies, and outline the remaining challenges for safely harnessing the autophagy–ICD axis in the clinical setting.