Reshaping the Battlefield: Reprogramming the Melanoma Tumour Microenvironment (TME) by Anti-CTLA-4, Anti-PD-1, and Anti-PD-L1 Monotherapy and Combination Therapy: A Systematic Review and Meta-Analysis of Preclinical and Clinical Evidence
Abstract
Immune checkpoint inhibitors (ICIs), comprising anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-programmed death-ligand 1 (PD-L1), have transformed melanoma therapy, yet the tumour microenvironment (TME), the pivotal biological interface where therapeutic efficacy, resistance, and toxicity are determined, remains incompletely characterized. This dual systematic review and meta-analysis (PROSPERO: CRD420261374242) followed PRISMA 2020 and included 58 preclinical (B16F10/C57BL/6; 46 quantitative) and 44 clinical studies (19 quantitative) to calculate pooled standardized mean differences (SMDs) for six intratumoral TME parameters. Checkpoint blockade consistently shifted the TME toward an immune-activated state, an effect that remained robust in sensitivity analyses despite substantial heterogeneity (I-squared heterogeneity statistic (I2) = 68-88%). Preclinically, ICIs significantly increased CD8+ T-cell infiltration (SMD = 1.45, p p p = 0.005), and apoptosis (SMD = 3.54, p p = 0.004) and Ki-67 (SMD = -1.43, p = 0.028). Clinically, CD8+ infiltration and PD-L1 both increased (SMD = 0.72, p p = 0.001), contrasting with the preclinical PD-L1 decrease. Meta-regression demonstrated superior anti-PD-L1 efficacy over CTLA-4 for effector parameters: IFN-γ +3.59 (p = 0.009), CD8/Treg +10.69 (p = 0.003), apoptosis +9.76 (p = 0.004), and Ki-67 -6.28 (p = 0.040). These findings establish the TME as a critical determinant of…
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