Overcoming resistance to T-cell-based immunotherapies

T-cell-based immunotherapies, including checkpoint inhibitors and engineered platforms such as CAR‑T and TCR‑modified T-cells, have reshaped cancer treatment by enabling precise immune recognition and tumor killing. Yet durable benefit remains inconsistent because resistance emerges from both tumor‑intrinsic alterations and tumor‑extrinsic constraints. Tumors evade immune pressure by losing or editing antigens, downregulating antigen‑presentation machinery, and reprogramming signaling pathways that blunt T‑cell cytotoxicity. The microenvironment further restricts efficacy through stromal barriers that limit trafficking, metabolic competition, and hypoxia that erode T‑cell fitness, and suppressive populations such as regulatory T-cells and myeloid‑derived cells that enforce dysfunction and exhaustion. These convergent processes reduce T-cell infiltration, persistence, and function across solid and hematologic malignancies. Defining the molecular circuits and ecological contexts that drive resistance is essential to designing rational combinations and next‑generation cell therapies capable of restoring durable, system‑wide antitumor immunity.The goal of this Research Topic is to assemble a coherent, cross‑disciplinary view of why T-cell-directed therapies fail and how to overcome those barriers. We aim to (i) clarify a mechanistic taxonomy of resistance spanning tumor, microenvironment, and T‑cell intrinsic programs; (ii) identify biomarkers and computational frameworks that predict benefit, guide sequencing, and enable adaptive treatment design; and (iii) highlight interventions that re‑establish trafficking, persistence, and cytotoxic function. We particularly seek studies that translate bench insights toward clinical solutions, including combination strategies (e.g., checkpoint plus metabolic or stromal modulators), next‑generation engineered T‑cell platforms (armored, synNotch/logic‑gated, or cytokine‑secreting designs), and approaches that recondition the microenvironment or reverse exhaustion states. By convening basic scientists, clinicians, and bioengineers, this collection intends to accelerate the development of more effective, personalized, and resilient T cell–based immunotherapies across solid and hematologic cancers.This Research Topic welcomes original research, reviews, brief reports, and perspectives that dissect primary or acquired resistance to T-cell-based immunotherapies, including checkpoint blockade, CAR‑T cells, TCR‑engineered T-cells, bispecific T‑cell engagers, and rational combinations. We invite studies on tumor‑intrinsic mechanisms (antigen escape, antigen‑processing/presentation loss, oncogenic signaling), T‑cell dysfunction (exhaustion, epigenetic programming, fitness, and persistence), trafficking and stromal barriers, metabolic competition, and immunosuppressive myeloid and stromal networks. Methodologies of interest include single‑cell and spatial multi‑omics, functional genomics and CRISPR screens, imaging‑based immune ecology, computational modeling, and biomarker discovery with prospective validation. We also encourage translational reports on early clinical innovations, e.g., armored or logic‑gated T-cells, engineered cytokines, synthetic circuits, and metabolism‑targeted combinations. Submissions should clearly articulate mechanistic insight and propose actionable strategies to improve potency, durability, and patient selection. Topic editors: Subhasis Das, Lucio Miele Source: https://www.frontiersin.org/research-topics/80061/overcoming-resistance-to-t-cell-based-immunotherapies