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Updated: May 9, 2026

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
09:32

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Published on: February 8, 2018

Taxane chemotherapy promotes response to TIM-3 checkpoint blockade via STING-mediated ER stress and HMGB1 secretion

Alexis Onimus1, Daiana Celias2, Shiun Chang3

  • 1Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA; Molecular Medicine PhD Program, University of South Florida, Tampa, FL 33620, USA.

Cell Reports. Medicine
|May 7, 2026
PubMed

Insights

Blocking TIM-3 with chemotherapy enhances anti-tumor immunity. Tumor cell HMGB1 release, triggered by taxanes via TLR4 and STING pathways, is crucial for this chemoimmunotherapy efficacy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) combined with chemotherapy show promise but mechanisms are unclear.
  • Previous work linked TIM-3 blockade and HMGB1-dependent DNA uptake to paclitaxel efficacy.
  • Understanding combinatorial therapy success factors is critical for cancer treatment.

Purpose of the Study:

  • To elucidate the role of High-Mobility Group Box 1 (HMGB1) release in chemoimmunotherapy efficacy.
  • To investigate the molecular mechanisms underlying HMGB1 release during taxane therapy.
  • To explore the involvement of the cGAS-STING pathway in chemoimmunotherapy.

Main Methods:

  • Investigated HMGB1 release in response to paclitaxel, docetaxel, fluorouracil, and irradiation.
  • Analyzed Toll-like receptor 4 (TLR4) signaling, reactive oxygen species production, and DNA damage.
  • Examined the cGAS-STING pathway activation, endoplasmic reticulum (ER) stress, and lysosomal exocytosis.

Main Results:

  • Tumor cell HMGB1 release is essential for combinatorial efficacy of TIM-3 blockade with taxanes, fluorouracil, and irradiation.
  • Taxane-induced HMGB1 release involves TLR4-dependent ROS production, DNA damage, and PARP activation.
  • STING activation by cytosolic DNA promotes ER stress and lysosomal exocytosis, driving HMGB1 secretion, but not type I interferons.

Conclusions:

  • HMGB1 release from tumor cells is a key mechanism for chemoimmunotherapy efficacy.
  • Taxane chemotherapy actively induces HMGB1 release through a non-canonical STING signaling pathway.
  • Targeting STING signaling could enhance the effectiveness of chemoimmunotherapy.
Keywords:
DNA damageHMGB1STINGTIM-3TLR4cGASchemotherapypaclitaxel

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