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Targeting organelle function in T cells for cancer immunotherapy

Nature Reviews Immunology (2025)Cite this article

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Abstract

Organelles are the internal batteries, gears, actuators, 3D printers and transmitters that drive cell function. Their composition and activity vary between cell types depending on functional demands. In T cells, which are key mediators of immunosurveillance and tumour eradication, organelles are relatively few and function at basal levels when cells are at rest. However, upon activation, they increase in number and size and undergo extensive remodelling to support rapid proliferation, effector differentiation and adaptation to diverse microenvironments, including the tumour microenvironment, thereby enabling efficient clearance of target cells. In this Review, we provide an overview of recent advances in our understanding of how various organelles contribute to T cell-mediated antitumour immunity. We also discuss emerging strategies to modulate organelle functions — from organelle-targeted therapies and their use as cargo delivery systems to the transfer or transplantation of native or synthetic organelles — that have the potential to enhance cancer immunotherapies involving immune-checkpoint blockade or the adoptive transfer of T cells.

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Fig. 1: Pharmacological and genetic engineering strategies to boost organelle function for improved cancer immunotherapy.
Fig. 2: Enhancing cancer immunotherapy by targeting mitochondrial transfer or transplantation.
Fig. 3: Generation of synthetic organelles.

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Acknowledgements

This work was supported by the DFG Reinhart Koselleck project (GA 2882/2-1). C.H.-L. is supported by the “T-FITNESS” Grant funded by the European Union under Grant agreement Number 101070740. J.G.B. was supported by a Fulbright Fellowship from the Australian Fulbright Commission and The Kinghorn Foundation and an Add-on Fellowship for Interdisciplinary Life Science from the Joachim Hertz Stiftung.

Author information

Authors and Affiliations

  1. Division of Functional Immune Cell Modulation, Leibniz Institute for Immunotherapy, Regensburg, Germany

    Jeremy G. Baldwin, Christoph Heuser-Loy & Luca Gattinoni

  2. Internal Medicine III — Haematology and Oncology, University Hospital Bonn, Bonn, Germany

    Christoph Heuser-Loy

  3. Center for Immunomedicine in Transplantation and Oncology, University Hospital Regensburg, Regensburg, Germany

    Luca Gattinoni

  4. University of Regensburg, Regensburg, Germany

    Luca Gattinoni

Authors
  1. Jeremy G. Baldwin
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  2. Christoph Heuser-Loy
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  3. Luca Gattinoni
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Contributions

J.G.B., C.H.-L. and L.G. conceived and wrote the manuscript. J.G.B. and C.H.-L. prepared the figures. L.G. contributed to refining the figures. All authors have read and approved the article.

Corresponding authors

Correspondence to Jeremy G. Baldwin or Luca Gattinoni.

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Competing interests

J.G.B. and L.G. have a patent application for the use of mitochondrial transfer technology in cancer immunotherapies. L.G. has consulting agreements with Lyell Immunopharma. L.G. is a scientific advisor and a stockholder of CellRep. C.H.-L. declares no competing interests.

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Nature Reviews Immunology thanks Shikhar Mehotra and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Autophagy

A cellular process by which cells break down and recycle their proteins and organelles to maintain intracellular homeostasis. The specific removal of mitochondria through autophagy is known as mitophagy.

Chimeric antigen receptor

(CAR). A synthetic surface receptor that typically consists of three key components: an extracellular antigen-recognition domain derived from a single-chain antibody variable fragment; an intracellular co-stimulatory domain (for example, CD28 or 4-1BB); and a CD3ζ cytoplasmic signalling domain for cell activation.

CRISPR screen

A genome-wide screening approach using the CRISPR–Cas9 gene editing system in combination with libraries of guide RNAs to delete or activate large numbers of genomic loci. Cells can be selected based on phenotype, and the corresponding guide RNA that is integrated into the genome can be identified by sequencing.

Epigenetic modifications

Modifications that alter gene expression and phenotype without affecting the DNA sequence. Epigenetic mechanisms include DNA methylation and modifications to histones such as methylation, acetylation or lactylation.

Heteroplasmy

The presence of at least two versions of mitochondrial genomes within one cell. Different genomes may carry mutations, and microheteroplasmy (<5% mutations) is common in eukaryotic cells.

Homoplasmy

Complete identity of all copies of the mitochondrial (or plastid) genome within one cell. Some tumour cells carry homoplasmically mutated mitochondrial genomes.

Immune synapse

The interface between an immune cell and a target cell (for example, a cancer cell) or an antigen-presenting cell (for example, a dendritic cell, macrophage or B cell).

Mechanistic target of rapamycin complex 1

(mTORC1). A multi-protein complex formed by the interaction of mTOR with DEPTOR, RPTOR, AKT1S1 and MLST8. mTORC1 is a crucial nutrient, energy and redox sensor within the cell. It regulates protein synthesis, cellular growth and metabolism by integrating signals from environmental cues such as nutrient availability and cellular energy levels.

MitoSnap

A transgenic mouse model system that enables tracking of mitochondria originating from the mother cell through the permanent fluorescent labelling of a SnapSubstrate that is specifically targeted to mitochondria by SYNJ2BP. Sequential labelling of SnapTag-expressing cells with different fluorescently labelled SnapSubstrates allows for the identification and sorting of distinct cell populations based on patterns of organelle inheritance.

Polysome

A polysome, or polyribosome, is a complex formed when multiple ribosomes simultaneously translate a single mRNA molecule. This arrangement allows for efficient, high-throughput protein synthesis.

Stem-like T cells

Minimally differentiated T cells that share characteristics with stem cells, including self-renewal and the capacity to differentiate into various functional T cell subsets. These cells can emerge following acute infections, where they are known as stem cell memory T cells, or in response to chronic inflammation and cancer, where they are referred to as precursor exhausted T cells.

Synthetic intramembrane proteolysis receptors

Engineered, Notch-based receptors activated by synthetic, bio-orthogonal or natural soluble ligands. Receptor activation depends on endocytosis and endosome acidification to elicit a cellular response.

T cell exhaustion

A dysfunctional T cell state caused by chronic infection or cancer that is marked by reduced proliferation, impaired effector function, increased expression of inhibitory receptors, and distinct transcriptional and epigenetic changes.

Tet-On system

A tetracycline-inducible bacteria-derived gene expression system. It consists of a reverse tetracycline transactivator that, in the drug (tetracycline)-bound state, binds to a tetracycline response element to induce expression of the downstream gene.

Tumour-infiltrating lymphocytes

(TILs). The heterogeneous population of lymphocytes found in a tumour. Their relative abundance, differentiation and functions depend on type, stage and location of the cancer. T cells isolated from TILs can be activated and expanded to large numbers ex vivo before re-infusion into patients with cancer for therapeutic purposes.

Tumour microenvironment

(TME). Tissue at the tumour site, consisting of cancer cells, blood vessels, immune cells and surrounding stromal cells, that, depending on the type of cancer, is often immunosuppressive and has physicochemical properties of hypoxia and low pH.

Unfolded protein response

(UPR). An endoplasmic reticulum stress response triggered by the misfolding of proteins inside the cell. The response can initiate repair mechanisms to correct misfolding such as upregulating chaperones, reducing overall protein synthesis to alleviate the burden, and promoting the degradation of misfolded proteins. If these repair mechanisms fail to resolve the stress, the UPR triggers cell apoptosis.

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Baldwin, J.G., Heuser-Loy, C. & Gattinoni, L. Targeting organelle function in T cells for cancer immunotherapy. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01223-9

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