Immune checkpoint therapy (ICT) has revolutionized cancer treatment by restoring cytotoxic T-cell activity, yet primary and acquired resistance remain pervasive. Increasing evidence reveals that such resistance is not dictated solely by tumor-intrinsic factors but arises from the dynamic interplay between malignant and stromal compartments within the tumor microenvironment. Among these, cancer-associated fibroblasts (CAFs)—the dominant stromal population—have emerged as key orchestrators of immune accessibility and therapeutic outcome. Beyond forming structural barriers through extracellular matrix remodeling, CAFs actively shape immune cell recruitment, polarization, and effector functions via diverse cytokines, chemokines, and metabolic pathways. In turn, immune-derived mediators reprogram CAF states, establishing bidirectional feedback circuits that continuously recalibrate stromal and immune homeostasis. These reciprocal networks transform the immune microenvironment into a self-adaptive ecosystem that governs tumor progression and responsiveness to ICT. This review synthesizes recent advances in understanding CAF–immune crosstalk, emphasizing how such interactions drive both primary and acquired resistance to checkpoint blockade. We further highlight emerging therapeutic strategies aimed at reprogramming the CAF–immune axis—rather than eradicating it—to restore durable and systemic antitumor immunity.
Wang et al. (Sun,) studied this question.