Targeting antibody-inaccessible immune resistance with small-molecule immunotherapy

ICIs have revolutionized cancer treatment; however, the achievement of sustained clinical benefits is confined to a subset of patients due to inherent and acquired resistance mechanisms. Accumulating evidence suggests that tumor immune evasion is often sustained through intracellular, metabolic, epigenetic, and myeloid-intrinsic pathways, which remain largely inaccessible to antibody-based therapies. These challenges underscore the necessity for supplementary immunotherapeutic approaches that extend beyond cell-surface checkpoint inhibition. Small-molecule immunotherapies present unique pharmacological advantages, such as enhanced tumor infiltration and the ability to target intracellular compartments. This capability facilitates the direct modulation of enzyme-dependent pathways and signaling networks that govern immune suppression within the TME. Recent advancements have unveiled a variety of small-molecule strategies aimed at targeting metabolic immune checkpoints, epigenetic regulators, innate immune sensing pathways, myeloid signaling, and immune checkpoint proteins through non-antibody modalities. Collectively, these strategies have the potential to reprogram the immunotherapy-resistant TME, restore the function of effector immune cells, and enhance responsiveness to ICIs. Clinical successes and failures, underscore the necessity for meticulous consideration of pathway redundancy, dosing, delivery, and biomarker-driven patient selection in the effective translation of small-molecule immunotherapy. Rather than serving as replacements for antibody-based ICIs, small-molecule immunotherapies act as mechanistically complementary agents that facilitate rational combination strategies targeting both surface and intracellular immune resistance mechanisms. In this review, we present a mechanistically integrated overview of small-molecule immunotherapies, examine key translational challenges, and explore future directions for overcoming immune resistance in cancer.