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Targeting macropinocytosis for cancer therapy

Nature Reviews Cancer (2025)Cite this article

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Abstract

Macropinocytosis is a nutrient-scavenging process that enables cells to engulf large volumes of extracellular fluid and solutes through dynamic plasma membrane ruffling. In cancer, this evolutionarily conserved process is frequently hijacked to meet the heightened metabolic demands of malignant cells, particularly under conditions of nutrient deprivation. Through macropinocytosis, tumour cells internalize diverse extracellular components — including proteins, nucleotides, lipids, ions and debris from dead cells — which are subsequently degraded in lysosomes and recycled to support biosynthesis and energy production. This process is tightly regulated by oncogenic signalling pathways and cues from the tumour microenvironment, including those associated with oncogene activation, loss of tumour suppressors and hypoxia. Beyond facilitating tumour growth and metabolic adaptation, macropinocytosis is implicated in resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy. When excessively activated, it can also lead to methuosis, a form of non-apoptotic cell death characterized by macropinosome overload. This Review outlines the molecular mechanisms and functional consequences of macropinocytosis in cancer, highlighting its dual potential as a metabolic vulnerability and a route for therapeutic delivery. Continued investigation into its regulation, context-specific roles and pharmacological modulation may uncover new opportunities for combination therapies and precision cancer treatment.

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Fig. 1: Key processes and regulatory pathways of macropinocytosis.
Fig. 2: Key oncogenic drivers and stress-responsive pathways that regulate macropinocytosis.
Fig. 3: Macropinocytosis as a mechanism of resistance to targeted therapy.

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Acknowledgements

The authors thank all of the pioneers in the field and their colleagues who have contributed to advancing the understanding of macropinocytosis. They apologize to those whose work could not be cited due to space limitations.

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Authors and Affiliations

  1. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Daolin Tang & Rui Kang

  2. Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiayi Wang

  3. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiayi Wang

  4. INSERM U1138, Équipe Labellisée — Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Paris, France

    Guido Kroemer

  5. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer

  6. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, Paris, France

    Guido Kroemer

Authors
  1. Daolin Tang
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  2. Jiayi Wang
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  3. Guido Kroemer
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  4. Rui Kang
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Daolin Tang, Jiayi Wang, Guido Kroemer or Rui Kang.

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Competing interests

G.K. has held research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio; is on the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences/Centenara Labs AG; and is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders (among these patents, ‘Methods for weight reduction’ (US11905330B1) is relevant to this study). G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. G.K.’s wife, L. Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9m, Tusk and Roche; was on the on the Board of Directors of Transgene; is a co-founder of everImmune; and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The other authors declare no competing interests.

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Glossary

Actin polymerization

The dynamic assembly of actin filaments that drive membrane protrusions, including ruffles and lamellipodia, that is essential for processes such as macropinocytosis, migration and intracellular trafficking.

Anchorage-independent growth

The ability of cells to proliferate without attachment to the extracellular matrix, often associated with tumorigenicity and supported by metabolic scavenging pathways.

Antigen presentation

The process by which antigen-presenting cells display processed peptide fragments on major histocompatibility complex (MHC) molecules to T cells, linking innate and adaptive immunity.

Autolysosomes

Vesicular structures formed from the fusion of an autophagosome with a lysosome, where enzymatic degradation of the sequestered material occurs.

Autophagosomes

Double-membrane vesicles that sequester cellular cargo for delivery to the lysosome during macroautophagy.

Autophagy

A catabolic process that delivers cytoplasmic components, including damaged organelles and macromolecules, to lysosomes for degradation and nutrient recycling.

Circular dorsal ruffle

A transient, ring-like membrane structure formed on the dorsal surface of cells that can function as an entry site for macropinosomes.

DAMPs

(Damage-associated molecular patterns). Endogenous molecules released from stressed or dying cells that activate immune responses by engaging pattern recognition receptors.

Endosomes

Membrane-bound intracellular vesicles that sort internalized cargo from the plasma membrane and direct it towards recycling, degradation or other trafficking routes.

ESCRT

(Endosomal sorting complex required for transport). A group of protein complexes involved in membrane remodelling events, such as multivesicular body formation, cytokinetic abscission and membrane repair.

Filamentous scaffolds

Cytoskeletal structures, primarily composed of actin or microtubules, that provide mechanical support and spatial organization for membrane trafficking and signalling processes.

Fluid-phase uptake

A non-selective internalization mechanism by which cells ingest solutes and nutrients dissolved in extracellular fluid.

Lysosomes

Acidic organelles containing hydrolytic enzymes that degrade macromolecules delivered by endocytosis, phagocytosis or autophagy to facilitate cellular recycling.

Macropinocytosis

An actin-driven, clathrin-independent endocytic process by which cells engulf extracellular fluid and solutes into large vesicles called macropinosomes.

Macropinolysosomes

Specialized intracellular vesicles formed by the fusion of macropinosomes and lysosomes.

Macropinosomes

Large, irregularly shaped intracellular vesicles formed by plasma membrane ruffling and closure, facilitating bulk nutrient uptake.

Membrane ruffling

Dynamic, actin-rich protrusions of the plasma membrane that initiate macropinocytosis in response to external stimuli such as growth factors or oncogenic signals.

Methuosis

A caspase-independent, non-apoptotic form of cell death caused by uncontrolled accumulation of large, fluid-filled macropinosomes and cytoplasmic vacuoles.

Necrocytosis

A macropinocytosis-mediated process to engulf necrotic debris, facilitating the acquisition of carbohydrates and fatty acids for energy production.

Nutrient scavenging

A metabolic adaptation that enables cancer cells to acquire essential nutrients from the extracellular environment under nutrient-deprived conditions.

Trophic support

The supply of essential growth factors, nutrients or metabolic signals that sustain cell viability, proliferation and differentiation.

WAVE regulatory complexes

(WASP family verprolin-homologous protein regulatory complexes). Multiprotein assemblies that activate the actin-related protein 2/3 (ARP2/3) complex to initiate branched actin polymerization, facilitating membrane ruffling and lamellipodia formation.

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Tang, D., Wang, J., Kroemer, G. et al. Targeting macropinocytosis for cancer therapy. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00892-x

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