Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies

Abstract

Simple Summary Immunotherapy drugs known as immune checkpoint inhibitors have improved outcomes for patients with squamous cell carcinomas of the head and neck, lung, esophagus, and skin, yet most patients still do not respond, even when their tumors look similar at the genetic level. Growing evidence points to a group of immune cells called myeloid cells as a key reason why. Tumors actively drive this reprogramming through tumor-derived cytokines, metabolites, and extracellular vesicles, while myeloid cells reciprocally shape tumor cell behavior through bidirectional crosstalk, together establishing a mutually reinforcing immunosuppressive circuit rather than a one-directional or passive process. In this review, we summarize how myeloid cells block anti-tumor immunity across these cancer types and examine emerging strategies, including radiation, drugs that activate innate immune signaling, and agents that target myeloid cells directly, aimed at reprogramming rather than simply eliminating these cells. We also discuss the toxicity, cost, and evidence gaps that must be addressed before these combination strategies can improve outcomes for patients with squamous cell carcinoma.