Programmed cell death‐1 blockade therapy in melanoma: Resistance mechanisms and combination strategies

Abstract

Melanoma is a highly aggressive tumor derived from melanocytes. In recent years, the incidence and mortality of melanoma have gradually increased, seriously threatening human health. Classic treatments like surgery, chemotherapy, and radiotherapy show very limited efficacy. Due to the high immunogenicity of melanoma cells, immune checkpoint inhibitors have received considerable attention as melanoma treatments.One such therapy is blockade of programmed cell death-1 (PD-1), which is one of the most important negative immune regulators and is mainly expressed on activated T cells. Disruption of the interactions between PD-1 and its ligands, programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) rejuvenates exhausted T cells and enhances antitumor immunity. Although PD-1 blockade therapy is widely used in melanoma, a substantial proportion of patients still show no response or short durations of remission. Recent researches have focused on revealing the underlying mechanisms for resistance to this treatment and improving its efficacy through combination therapy. Here, we will introduce the resistance mechanisms associated with PD-1 blockade therapy in melanoma and review the combination therapies available.

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1‐dependent reduction of esterified cholesterol

“…T cell-derived IFN-γ amplifies the T cell response in immunotherapies such as anti-PD-1 antibody therapy. 30,31 Combination of either SCD1 inhibitors or ACAT1 inhibitors with anti-PD-1 mAbs showed synergistic antitumor effects (Figure 3D,E), indicating that interventions on SCD1-ACAT1 axis in CD8 + T cells may be useful for the development of combination immunotherapy.…”

PANoptosis‐related signature in melanoma: Transcriptomic mapping and clinical prognostication

“…While the burgeoning field of PANoptosis in cancer is gaining momentum, a notable gap exists in our understanding of its specific role in melanoma 11 . Melanoma, an aggressive form of skin cancer notorious for its metastatic potential and resistance to conventional therapies, poses a unique challenge in the realm of cell death research 12–14 . Despite the growing recognition of the importance of cell death pathways in melanoma, investigations specifically centered on PANoptosis in this context remain scarce.…”

“…11 Melanoma, an aggressive form of skin cancer notorious for its metastatic potential and resistance to conventional therapies, poses a unique challenge in the realm of cell death research. [12][13][14] Despite the growing recognition of the importance of cell death pathways in melanoma, investigations specifically centered on PANoptosis in this context remain scarce. This manuscript seeks to address this knowledge gap by providing a comprehensive overview of the current understanding of PANoptosis in melanoma, leveraging cutting-edge sequencing technologies to decipher the role of PANoptosis in shaping the clinical outcomes of patients.…”