Rare and immunologically cold solid tumors: T cell-engaging strategies for sarcoma, lung cancer, and beyond

Many solid tumors, and sarcomas, lung cancers, and rare tumor types in particular, remain among the most immunologically resistant malignancies, and immune checkpoint inhibitors, which have transformed outcomes in more immunogenic epithelial cancers, have shown only modest or inconsistent benefit across these histotypes. This limited response reflects shared features of their immunobiology: sparse or heterogeneous T cell infiltration, variable tumor mutational burden, and an immunosuppressive stroma that actively excludes effector cells. Overcoming these barriers increasingly depends not on releasing brakes on pre-existing T cell responses, but on actively redirecting or delivering T cell activity into microenvironments that do not readily support it on their own.A new generation of T cell-engaging modalities is beginning to address this challenge directly. Bispecific antibodies and T cell engagers can physically bridge cytotoxic T cells to tumor-associated antigens independent of native antigen presentation, bypassing a major limitation in poorly infiltrated tumors. Antibody-drug conjugates offer a complementary strategy, using tumor-selective targeting to deliver cytotoxic payloads that can both kill tumor cells directly and reshape the surrounding immune landscape through immunogenic cell death. Alongside these, engineered TCR-T cell and CAR-T approaches targeting tumor-specific or tumor-associated antigens are advancing through early clinical evaluation across sarcoma, lung cancer, and other rare or difficult-to-treat solid tumors. Understanding how these modalities interact with, and are shaped by, the tumor microenvironment, including stromal density, myeloid infiltration, and antigen heterogeneity across histotypes, is essential to translating early clinical signals into durable benefit.This Research Topic invites original research, mechanistic studies, and reviews focused on T cell-engaging and TME-directed therapeutic strategies across solid tumors, with a particular focus on sarcoma, lung cancer, and rare tumor types. Topics of interest include, but are not limited to:• Design and preclinical or clinical evaluation of bispecific antibodies and T cell engagers targeting tumor-associated antigens in sarcoma, lung cancer, and rare solid tumors• Antibody-drug conjugates in solid tumors: target selection, payload mechanisms, and immune-mediated effects beyond direct cytotoxicity• Engineered TCR-T and CAR-T cell approaches for solid tumors, including antigen selection and strategies to improve tumor infiltration• Mechanisms by which the tumor microenvironment (stromal architecture, myeloid populations, antigen heterogeneity) limits or shapes T cell-engaging therapy efficacy across histotypes• Combination strategies pairing T cell-engaging therapies with TME-modulating agents to improve response in sarcoma, lung cancer, and rare tumors• Biomarkers predictive of response or resistance to T cell-redirecting therapies across solid tumor typesWe welcome contributions spanning sarcoma, lung cancer, and rare or underrepresented tumor types, with a particular interest in mechanism-based studies that clarify how these modalities perform within the distinct immunobiology of each.Dr. Benjamin A. Bleiberg declares the following potential competing interests: he serves on the steering committee for a clinical study with Johnson & Johnson; has received honoraria and travel funding from MJH Life Sciences; has previously participated in an advisory board for Pharmacosmos; provides advisory services to Senticell; is an Open Medicine Foundation Circle Member with stock options; and has received research funding from Valar Labs and Guardant Health. Topic editors: Emanuela Palmerini, Chinmay Jani, Benjamin A Bleiberg Source: https://www.frontiersin.org/research-topics/85674/rare-and-immunologically-cold-solid-tumors-t-cell-engaging-strategies-for-sarcoma-lung-cancer-and-beyond