PSGL-1 blockade delays relapse to BRAF/MEK inhibition in cutaneous melanoma

Advanced BRAF-mutant cutaneous melanoma can be treated with targeted therapy when immune checkpoint inhibitors (ICIs) fail or are not a feasible option. Nevertheless, most patients do not achieve a durable response, highlighting the critical need for therapeutic partners that enhance the long-term efficacy of targeted therapy. Transcriptomic analysis of a BRAF-mutant melanoma model of acquired resistance identified P-selectin glycoprotein ligand-1 (PSGL-1) as a top-upregulated immune mediator upon resistance acquisition. PSGL-1 is a key regulator of CD8 ⁺ T cell exhaustion and differentiation, and its inhibition has been shown to enhance T cell function across multiple disease models. Based on these observations, we hypothesized that combined targeting of BRAF/MEK and PSGL-1 would improve anti-tumor responses. Here, we demonstrate that dual inhibition of BRAF/MEK and PSGL-1 elicits durable tumor control in a preclinical model of PD-1-refractory cutaneous melanoma. Single-cell RNA sequencing of the tumor microenvironment reveals robust reprogramming of intratumoral CD8 ⁺ T cells toward a less terminally differentiated, memory-like phenotype following combined BRAF/MEK and PSGL-1 targeting. Consistent with these findings, CD8 ⁺ T cells in the tumor-draining lymph nodes of PSGL-1 ^-/- mice exhibit enhanced functionality and a less differentiated state of exhaustion when compared with wild-type mice. To extend these observations to a translationally relevant setting, we further show that antibody-mediated blockade of PSGL-1, in combination with BRAF/MEK inhibition, yields superior anti-tumor activity compared with either monotherapy. Collectively, these findings identify PSGL-1 as a promising therapeutic target to enhance the durability of targeted therapy and provide a strong rationale for future clinical evaluation.