Figure 7. The ATX/LPA axis is upregulated with anti–PD-(L)1 treatment resistance, modulating CD8⁺ T cell functionality via LPAR5 activation.

Kras/p53 mutant lung cancers respond initially to PD-1/PD-L1 axis blockade, but eventually acquire resistance. Our data indicate that a robust and stable upregulation of the enzyme autotaxin (ATX) occurs with resistance, which causes an aberrant accumulation of its bioactive metabolite, lysophosphatidic acid (LPA). LPA acts in a paracrine manner on tumor-resident immune cells, particularly the CD8⁺ T cell compartment. Activation of LPA receptor 5 (LPAR5) via LPA diminishes T cell receptor signaling and downstream activation required for effective antitumor functionality, thereby promoting tumor cell survival. Targeting ATX or LPAR5 with anti–PD-1 treatment can promote antitumor immunity by restoring T cell proliferation and activation, leading to more efficacious control of lung cancer growth.