A review of soluble mediator and cytokine networks linking combination immunotherapy, tumor microenvironment remodeling and skeletal muscle dysfunction

Clinical Medicine and Integrative Therapies

Cytokine circuitries as determinants of response, resistance, and toxicity across cancer immunotherapy platforms.

Cancer immunotherapy has substantially improved the management of solid tumors and hematologic malignancies; however, durable clinical benefit remains limited by primary and acquired therapeutic resistance, immune-related toxicities, and considerable interpatient heterogeneity. Although cytokines, chemokines, and growth factors have been extensively investigated as predictive and prognostic biomarkers, their coordinated functions within dynamic immune networks remain insufficiently integrated into current translational and clinical frameworks. The purpose of this review is to critically evaluate emerging evidence supporting cytokine network dynamics and to introduce adaptive cytokine circuitries as a conceptual framework for understanding how interconnected cytokine signaling regulates therapeutic response, resistance, and toxicity across immune checkpoint blockade, chimeric antigen receptor T-cell therapy, T-cell receptor-engineered therapies, bispecific antibodies, and emerging cellular immunotherapies. Current evidence indicates that cytokine interactions operate through spatially and temporally organized signaling networks that influence T-cell functional states, myeloid cell reprogramming, immune escape, and tissue-specific inflammatory responses, while highlighting important biological uncertainties and the need for prospective clinical validation. The review further examines the translational potential of longitudinal immune monitoring, multiplex cytokine profiling, spatial and single-cell multi-omic technologies, computational network reconstruction, and biomarker-guided patient stratification for precision immunotherapy. Collectively, the available evidence supports a transition from static cytokine measurements toward dynamic cytokine network analysis while underscoring the scientific and clinical challenges that must be addressed before cytokine circuitry-informed strategies can be implemented in precision immuno-oncology.

KRAS-driven cytokine–metabolic crosstalk shapes immune exclusion in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy, frequently characterized by an immune-excluded tumor microenvironment (TME). Oncogenic KRAS mutation, the predominant genetic driver in PDAC, serves as a master upstream regulator linking tumor-intrinsic signaling with microenvironmental remodeling. Through reshaping cytokine secretion and metabolic programs, mutant KRAS coordinates inflammatory and metabolic networks within the TME. Specifically, KRAS-linked cytokine networks, including tumor-cell-intrinsic mediators such as GM-CSF and microenvironment-associated inflammatory signals involving CXCLs, IL-6, TGF-β, and IL-1β, interact reciprocally with metabolic alterations, such as glycolytic activation, lactate accumulation, hypoxia adaptation, adenosine signaling, and altered amino acid and lipid metabolism. These pathways converge on shared regulatory nodes, notably STAT3, NF-κB, HIF-1α, and MYC, to drive immunosuppressive myeloid cell accumulation, stromal cell activation, extracellular matrix deposition, and restricted CD8 + T-cell infiltration. Furthermore, lactate, adenosine, and physical stromal barriers reinforce these immunosuppressive cascades, thereby establishing spatial immune exclusion. This review summarizes recent evidence on KRAS-driven cytokine–metabolic crosstalk in PDAC and discusses how this genotype-associated regulatory pattern governs immune exclusion, offering novel insights into overcoming immunotherapy resistance.

Remodeling the tumor immune microenvironment: mechanisms of crosstalk between regulated cell death macrophages

Although advances have been made in tumor immunotherapy, the immunosuppressive tumor microenvironment and treatment resistance still limit durable clinical benefit. Rather than functioning exclusively as terminal cytotoxic phenomena, regulated cell death (RCD) pathways generate surface cues, soluble mediators and cellular cargo that reshape immune responses. Here, we review the reciprocal interactions linking tumor-associated macrophages (TAMs) with apoptosis, necroptosis, pyroptosis, autophagy-related regulation, ferroptosis and cuproptosis. We examine how death execution, the kinetics and magnitude of tumor cell death, membrane integrity, and signal accessibility shape RCD-derived signals, and how macrophage lineage, functional state and signal-processing capacity determine their inflammatory and antitumor consequences. These reciprocal interactions regulate corpse clearance, antigen presentation, metabolic adaptation, tumor progression, and therapeutic resistance, while macrophages can in turn alter the susceptibility of viable tumor cells to death. We further discuss crosstalk among RCD pathways, extracellular vesicle-mediated communication, microbiota-related regulation and spatiotemporal reconfiguration during tumor progression and treatment. Finally, we evaluate nanomedicine strategies that coordinate tumor-selective RCD with macrophage regulation while emphasizing limitations in cell-type specificity, safety, patient selection and clinical evidence. This framework may guide more precise intervention along the RCD–macrophage axis.

Reprogramming tumor-associated macrophages and interferon-gamma signaling to overcome therapeutic resistance in cancer.

Therapeutic resistance remains a major obstacle in cancer treatment and limits the durability of immunotherapy, chemotherapy, and targeted therapy. Tumor-associated macrophages (TAMs) contribute to resistance through spatially and functionally heterogeneous programs shaped by hypoxia, vascular niches, metabolic stress, tumor-derived signals, and therapy-induced inflammation. Chronic IFN-γ exposure can also promote adaptive resistance through checkpoint induction, altered antigen presentation, suppressive feedback signaling, metabolic rewiring, and epigenetic remodeling. This review examines how TAM heterogeneity and IFN-γ signaling intersect to support therapy evasion, with emphasis on macrophage niches, phagocytosis resistance, lactate-associated epigenetic regulation, and clinically relevant feedback loops. We also discuss why several TAM-directed strategies, including CSF1R inhibition, have shown stronger activity in preclinical models than in clinical trials. Finally, we evaluate emerging approaches such as macrophage reprogramming, CD47/SIRPα blockade, CAR-macrophage engineering, and biomarker-guided combination therapy. A clearer understanding of TAM states, spatial context, and IFN-γ dynamics may improve patient stratification and support more rational translational strategies to overcome therapeutic resistance.

ADAM12 in a stromal-checkpoint framework: integrating tumor microenvironment remodeling and therapy resistance in solid tumors

The tumor microenvironment (TME) is now understood as an active regulator of therapeutic vulnerability. In this Review, we use an integrative stromal-checkpoint framework, informed by published stromal and fibroblast checkpoint studies, to describe stromal programs that couple extracellular matrix (ECM) remodeling, metabolic stress, vascular dysfunction, and immune exclusion into treatment-resistant tumor ecologies. We focus on a disintegrin and metalloproteinase 12 (ADAM12) because ADAM12-high or ADAM12-positive tumor-stromal states have been linked to collagen-rich desmoplasia, mechanotransduction, hypoxia-associated stress, lactate-associated acidosis, immune-excluded spatial organization, and therapy resistance in solid tumors. Evidence spans fibroblast, mesenchymal stromal-cell, and tumor-cell perturbation studies; mechanistic substrate and signaling analyses; spatial and clinical datasets; and broader tissue-level immune contexts relevant to lymphatic drainage, tumor-draining lymph node (TDLN) priming, tissue-resident immune cells, and ILC2/type 2 immune programs. Across these evidence layers, ADAM12 emerges as an isoform-aware and cell-of-origin-dependent marker, amplifier, and context-dependent candidate target for selected high-barrier tumor states. We discuss how ADAM12-informed biomarkers, spatial barrier profiling, and stromal-priming strategies can support patient stratification and combination-therapy design. Overall, ADAM12-associated biology provides a useful model for examining how stromal resistance may be built, maintained, and therapeutically remodeled in selected tumor contexts.