Furthermore, therapeutic delivery of Galunisertib using choline-modified lipid nanoparticles synergizes with αPD-1, fostering the conversion of exhausted CD8⁺ T cells into responsive Ly108⁺CX3CR1⁺ subsets and suppressing liver metastases. Collectively, our results identify hepatocyte TGFβ signaling as a targetable checkpoint against liver metastases.

P1/2, N=21, Completed, ImmunityBio, Inc. | Active, not recruiting --> Completed | N=60 --> 21

P2, N=375, Recruiting, Avalyn Pharma Inc. | Trial completion date: Apr 2026 --> Jun 2027 | Trial primary completion date: Apr 2026 --> Jun 2027

P1, N=18, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> Feb 2025

P2, N=92, Active, not recruiting, Gradalis, Inc. | Trial completion date: Dec 2025 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2028

Although these targeted therapies show potential to overcome resistance and improve patient outcomes, challenges remain due to the complex regulation of EMP. Future directions focus on refining combination strategies and advancing personalized approaches to enhance efficacy across multiple cancer types.

P1, N=4, Terminated, M.D. Anderson Cancer Center | N=64 --> 4 | Trial completion date: Jan 2027 --> Sep 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2027 --> Sep 2025; <75 % participation

The formulation co-delivered NMS-873 (NM), a VCP/p97 inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME...In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

P2, N=52, Recruiting, Scholar Rock, Inc. | Not yet recruiting --> Recruiting

TGF-β receptor I kinase plays a significant role in cancer biology and is a well-established target for cancer drug development, as evidenced by active molecules like Galunisertib (LY2157229)...Molecular Dynamics simulation study indicated that specific aminoacid residue interaction with TGF-β receptor I kinase. Additionally, DFT calculations were conducted on the active molecules to gain deeper insights into their electronic properties, supporting their potential as effective anticancer agents.

These hits exhibited lower free energies (ΔG) as compared to the benchmark inhibitors, Galunisertib and Vactosertib. The results offer valuable insights into the binding mechanism of protein TGFßR1 and its role in the disease, suggesting that targeting the TGF-ß signaling pathway may represent a promising therapeutic strategy.

EGFR-directed cellular therapies, particularly EGFR CAR-NK cells, demonstrate activity against EGFR-mutant DTPCs and DRCs in vitro and in vivo, with enhanced activity observed when combined with EGFR TKIs or TGF-β pathway blockade.