Cancer-associated adipocytes mediate CD8⁺T cell dysfunction via FGF21-driven lipolysis

Area of Science:

• Cancer biology
• Immunology
• Metabolic research

Background:

• Cancer-associated adipocytes (CAAs) influence the tumor microenvironment (TME).
• The metabolic interactions between CAAs and CD8+ T cells are not fully understood.
• CD8+ T cells are crucial for anti-tumor immunity.

Purpose of the Study:

• To investigate the metabolic crosstalk between CAAs and CD8+ T cells.
• To identify mechanisms by which CAAs affect CD8+ T cell function.
• To explore therapeutic strategies targeting CAA metabolism for cancer immunotherapy.

Main Methods:

• Investigated lipolysis in CAAs and its impact on CD8+ T cells.
• Utilized FGF21 deletion models and ATGL inhibition.
• Assessed mitochondrial homeostasis and effector functions of CD8+ T cells.
• Evaluated tumor growth and response to anti-PD-1 therapy.

Main Results:

• CAAs release free fatty acids via lipolysis, causing lipid peroxidation and mitochondrial dysfunction in CD8+ T cells, leading to exhaustion.
• FGF21 promotes CAA lipolysis by upregulating ATGL through FGFR1/KLB-p38 signaling.
• FGF21 deletion or ATGL inhibition restored CD8+ T cell function and suppressed tumor growth.
• Targeting CAA lipolysis enhanced anti-tumor immunity and efficacy of anti-PD-1 therapy.

Conclusions:

• CAA lipolysis is a key mechanism of CD8+ T cell dysfunction in the TME.
• Targeting CAA lipolysis, particularly FGF21/ATGL pathways, is a promising strategy to improve cancer immunotherapy.
• Restoring CD8+ T cell effector function via metabolic reprogramming offers a novel therapeutic avenue.