fig6

Figure 6. Potential factors influencing PD-1/PD-L1 inhibitor response. Multiple factors within both the macro- and microenvironments interact to regulate antitumor immunity and responses to PD-1/PD-L1 inhibitors. Microenvironmental factors involve elements affecting antigen release, antigen presentation, immune cell activation, and metabolism. Macroenvironmental factors include age, sex, microbiome, diet, and exercise. Recently, the influence of neuroimmune interactions on antitumor immunity has been increasingly recognized, suggesting additional potential targets for overcoming resistance. PD-1: Programmed death-1; PD-L1: programmed death-ligand 1; ADC: antibody-drug conjugate; HDACi: histone deacetylase inhibitor; BETi: bromodomain and extraterminal inhibitor; APC: antigen-presenting cell; DC: dendritic cell; ECM: extracellular matrix; LOX: lysyl oxidase; MMPs: matrix metalloproteinases; CAF: cancer-associated fibroblast; FAK: focal adhesion kinase; DDR: discoidin domain receptor; Tex: exhausted T cell; Treg: regulatory T cell; TADC: tumor-associated dendritic cell; MDSC: myeloid-derived suppressor cell; IFNγ: interferon gamma; β2M: beta-2 microglobulin; TCR: T cell receptor; GABA: gamma-aminobutyric acid; TNF-α: tumor necrosis factor alpha; β1-AR: beta-1 adrenergic receptor; β2-AR: beta-2 adrenergic receptor; NE: norepinephrine; SLPI: secretory leukocyte protease inhibitor; CGRP: calcitonin gene-related peptide; Ach: acetylcholine; NK: natural killer; CA: cancer cell; Teff: effector T cell; TAM: tumor-associated macrophage; N: neutrophil; MAMPs: microbe-associated molecular patterns; ICI: immune checkpoint inhibitor; XCI-E: X-chromosome inactivation escape; LOY: loss of Y chromosome; irAE: immune-related adverse event; TMB: tumor mutational burden; HAPLN1: hyaluronan and proteoglycan link protein 1; GDF15: growth differentiation factor 15; CXCL12: C-X-C motif chemokine ligand 12; ICAM1: intercellular adhesion molecule 1.