{
  "abstract": "Extracellular acidosis is a hallmark of aggressive tumors and suppresses cytotoxic-T lymphocyte (CTL)-mediated killing, but how sustained acid exposure reshapes T cell cytotoxicity is poorly understood. Here we show that chronic acidosis drives lysosomal remodeling in human CD8+ T cells, converting the lysosome into a proton sink whose adaptation ultimately impairs killing by depleting the intracellular granzyme B reservoir through constitutive vesicle release. Quantitative proteomics of CD8+ T cells cultured at pH 6.5 identified lysosomes as the dominant target of acid-driven remodeling: CTLs upregulated the V1 sector of the vacuolar H+-ATPase and hyper-acidified the lysosomal lumen. The remodeled compartment accumulated lysosomal membrane proteins (LAMP1, LAMP2, CD63, CD68) post-transcriptionally, acquired higher cathepsin abundance and increased proteolytic activity. Chronic acidity also enlarged endoplasmic reticulum (ER) and lysosomal Ca2+ stores without altering cytosolic Ca2+, and drives constitutive, Ca2+-dependent release of LAMP1+ lysosome-derived vesicles, which drains the intracellular reservoir of granzyme B, contributing to reduced CTL activity. These findings establish lysosomal adaptation as a cost of surviving extracellular acidosis and identify lysosomal hydrolase activity as a possible target for improving CTL function in the acidic tumor environment.",
  "abstract_shown": true,
  "affiliations": [
    "Inserm"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "B. Segain"
    },
    {
      "name": "R. Conesa"
    },
    {
      "name": "C. Rollings"
    },
    {
      "name": "S. Titah"
    },
    {
      "name": "E. Paulin"
    },
    {
      "name": "A. Cozzani"
    },
    {
      "name": "A. Kasprowicz"
    },
    {
      "name": "L. Mohammadnizad"
    },
    {
      "name": "S. Gaggero"
    },
    {
      "name": "Y. Touil"
    },
    {
      "name": "I. Moraga"
    },
    {
      "name": "B. Quesnel"
    },
    {
      "name": "R. Roychoudhuri"
    },
    {
      "name": "R. Eil"
    },
    {
      "name": "L. V. Sinclair"
    },
    {
      "name": "J. Martinez"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Mitra"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d9qgpzxeeybb0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.21.760659",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1.full",
  "id": "d9qgpzxeeybb0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2713|Autophagy in Disease and Therapy"
    ]
  ],
  "openalex": "W7224012355",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-21",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/d9qgpzxeeybb0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:48Z",
      "native_id": "10.64898/2026.10.21.760659",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760659v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity",
  "title_text": "Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:48Z",
  "url": "https://research.draconitic.com/paper/d9qgpzxeeybb0",
  "venue": "bioRxiv",
  "versions": []
}