Enhancing cancer care with improved checkpoint inhibitors: a focus on PD-1/PD-L1

Abstract

The emergence of checkpoint inhibitors targeting the PD-1/PD-L1 axis marks a paradigm shift in cancer therapy, offering a novel avenue for enhancing patient outcomes. This review examines the structural and functional dynamics of PD-1 and PD-L1 while exploring the clinical implications of current PD-1/PD-L1 monoclonal antibodies. Highlighting recent advancements, this paper delves into the promising results from combination therapies that present a multifaceted attack on tumor progression. Despite the success observed across various cancer types, challenges such as immune resistance remain. Future considerations are discussed with an emphasis on the need for further clinical studies, aiming to refine and broaden the curative potential of PD-1/PD-L1 inhibitors in oncology. This review postulates that ongoing research and innovative approaches could significantly enhance cancer care, making immunotherapy an even more central strategy in the fight against cancer. See also the graphical abstract(Fig. 1).

Keywords: PD-1; PD-L1; cancer; checkpoint inhibitors; immunotherapy.

Table 1. FDA-approved immune checkpoint inhibitors and their indications across various tumor types

Table 2. Mode of action of anticancer agents in melanoma and their correlation with response patterns and safety characteristics

Figure 1. Graphical abstract

Figure 2. Reactivation of T-cell function by PD-1/PD-L1 inhibitors and the role of T-cell receptors, antigens, and MHC

Figure 3. Mechanism of action: PD-1/PD-L1 inhibitors and their role in enhancing anti-tumor immunity

Figure 4. (a) The regulation of PD-1/PD-L1 expression involves multiple pathways. The PI3K/AKT pathway, MAPK pathway, JAK/STAT pathway, WNT pathway, NF-κB pathway, and Hedgehog (Hh) pathway collectively stimulate the expression of the PD-1/PD-L1 axis. (b) Impact of PD-1/PD-L1 immune checkpoint engagement on T-cell fate. The interaction between PD-1 and PD-L1 triggers phosphorylation within PD-1's ITIMs and ITSMs, prompting the association with SHP-2 phosphatase. This interaction inhibits the PI3K/AKT and Ras/MAPK/ERK pathways, culminating in T-cell apoptosis.