Cellular Pharmacology of Anti-Cancer Immunomodulators: Mechanisms of Sensitivity and Resistance Across the Tumor Ecosystem

The tumor microenvironment represents a complex cellular ecosystem where immune, stromal, and malignant cells dynamically interact under therapeutic pressure. Immunomodulatory drugs—including checkpoint blockade antibodies, small molecules, and combination regimens—can profoundly alter these interactions. However, distinct cell populations often exhibit heterogeneous pharmacodynamic responses, leading to partial efficacy or acquired resistance. Recent advances in single-cell sequencing, proteomic imaging, and systems pharmacology have revealed that even phenotypically similar immune cells respond differently to the same therapeutic stimulus. Understanding these cell-specific pharmacological behaviors is crucial to explain why immunotherapies succeed in some patients yet fail in others. This Research Topic focuses on decoding such heterogeneity to guide rational drug design and optimized treatment combinations.The goal of this Research Topic is to define how anti-cancer immunomodulators exert cell type–specific pharmacological effects within the tumor ecosystem and to elucidate the mechanisms that underlie therapeutic sensitivity and resistance. Immune checkpoint inhibitors, cytokine modulators, and myeloid-targeted agents have reshaped cancer therapy, yet variable patient responses remain a major obstacle. This initiative seeks to uncover how these drugs remodel immune and stromal cell subsets, reprogram intercellular signaling, and drive adaptive resistance. By integrating single-cell pharmacogenomics, spatial profiling, and advanced computational modeling, the Topic aims to build predictive frameworks that connect molecular drug actions to system-level immune outcomes. Through these efforts, we expect to establish a mechanistic foundation for next-generation immunomodulators that achieve durable efficacy while minimizing immune-related adverse events.We welcome Original Research, Reviews, Methods, and Perspective articles addressing cellular and molecular pharmacology of anti-cancer immunomodulators, but are not limited to, the following themes:• Single-cell and spatial pharmacoprofiling of tumor and immune subsets.• Mechanisms of cellular sensitivity and resistance to immunomodulatory drugs.• Pharmacological modulation of the tumor microenvironment and immune exhaustion.• Computational modeling of drug–cell interaction networks.• Biomarker discovery for predicting immunomodulator efficacy and toxicity.• Development of targeted or combination strategies to overcome immune resistance.• Translational studies linking preclinical pharmacology to clinical response heterogeneity.This Topic provides a multidisciplinary forum bridging pharmacology, immunology, systems biology, and translational oncology to advance precision immunotherapy.Please note:1. The journal endorses protocols including a minimum of 2 cell-lines in vitro as an evidential basis to demonstrate proposed anti-cancer effects in all relevant studies submitted to all specialty sections in the journal.2. Studies that are purely statistical or predictive in nature, without providing novel insights into pharmacological mechanisms or drug development, are not within the scope of this journal.3. Frontiers’ journals require that manuscripts primarily comprising computational studies of public data, such as NHANES or Mendelian Randomization studies, must include appropriate validation. Please refer to the Frontiers Standards for research methodology policy, for more information. Manuscripts not adhering to these standards will not be considered. Topic editors: Dawei Chen, Changchang Jia, HUICHAO ZHOU Source: https://www.frontiersin.org/research-topics/76094/cellular-pharmacology-of-anti-cancer-immunomodulators-mechanisms-of-sensitivity-and-resistance-across-the-tumor-ecosystem