(1) Journal Source: Biomaterials

(2) Title: Enhancing neoadjuvant immunotherapy for locally advanced rectal cancer via an injectable thermosensitive hydrogel system with multipathway macrophage immunomodulation

(3) Research Highlights: This study designed an injectable thermosensitive PLEL hydrogel for transanal administration, co-loaded with oxaliplatin, anti-CD47 antibody and CpG. It achieves localized sustained drug release through multipathway macrophage immunomodulation. The immune remodeling capacity of this system was investigated at the cellular level and in orthotopic rectal cancer models, and its efficacy for neoadjuvant immune intervention against locally advanced rectal cancer was evaluated.

(4) Innovations: ① An in-situ gelling injectable thermosensitive PLEL hydrogel was adopted for transanal intratumoral administration to retain drugs locally at the lesion site; ② Chemotherapeutic agents, phagocytic checkpoint blocking antibodies and immune adjuvants are co-delivered to construct a synergistic strategy of "priming-inhibition reversal-activation"; ③ Tumor-associated macrophages are regulated via multiple pathways to promote M1 polarization and boost phagocytic capacity, further driving dendritic cell maturation and systemic CD8⁺ T cell responses; ④ Animal models verified that this system can reduce preoperative tumor burden, improve surgical conditions and induce the formation of immune memory.

(5) Material Development (1) Materials: Thermosensitive hydrogel matrix of PDLLA‑PEG‑PDLLA (PLEL) amphiphilic triblock copolymer; oxaliplatin (OXA), αCD47 antibody and CpG oligonucleotides are co-loaded to obtain the OXA/αCD47/CpG@PLEL composite hydrogel. (2) Functions: Injectable at room temperature and undergoes sol‑gel phase transition under physiological temperature to realize localized sustained drug release; oxaliplatin induces immunogenic cell death of tumor cells; αCD47 blocks the "don’t eat me" signal; CpG reprograms macrophage phenotypes; the components synergistically remodel the tumor immune microenvironment and activate innate and adaptive anti-tumor immunity.

(6) Outlook for Further Research: The complete molecular crosstalk between innate immunity and adaptive immunity can be further elucidated; the synergistic effects under different drug loading ratios can be systematically explored; this drug delivery platform can also be expanded to accommodate more immunologically active components.

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